Effects of oxygen tension on gene expression in preimplantation mouse embryos

Effects of oxygen tension on gene expression in preimplantation mouse embryos Paolo F. Rinaudo, M.D., Ph.D.,a,b Gnanaratnam Giritharan, D.V.M., Ph.D.,b Said Talbi, Ph.D., DBA,b Anthony T. Dobson, M.D., Ph.D.,b and Richard M. Schultz, Ph.D.a a

Department of Biology, University of Pennsylvania, Philadelphia, Pennsylvania, and b Department of Obstetrics and Gynecology, University of California-San Francisco, San Francisco, California

Objective: To compare the effects of atmospheric and physiologic oxygen concentrations on the global patterns of gene expression during mouse preimplantation development. Design: Comparative analysis of in vivo–produced and in vitro–produced embryos. Setting: Research laboratory. Patient(s): None. Intervention(s): Control embryos at the blastocyst stage that developed in vivo were collected from uteri. Experimental embryos were obtained at the zygote stage and cultured to the blastocyst stage in Whitten’s medium or KSOM medium with amino acids under 20% oxygen (atmospheric) or 5% oxygen (physiologic). Main Outcome Measure(s): Embryo development, cell number, and gene expression assayed by microarray technology. Result(s): Low (physiologic) oxygen concentration is associated with faster embryo development and increased cell number. In addition, there are marked perturbations in the global pattern of gene expression, as assessed by oligonucleotide microarray, after culture in 20% oxygen as compared with 5% oxygen. Conclusion(s): Culture in low oxygen is associated with fewer perturbations in the global pattern of gene expression and more closely resembles that of the in vivo control embryos. These findings provide rationale for culturing human embryos in the presence of 5%, rather than 20%, oxygen. (Fertil Steril威 2006;86(Suppl 3): 1252– 65. ©2006 by American Society for Reproductive Medicine.) Key Words: Microarray, gene expression, culture media, blastocyst, IVF, oxygen

Although the increase in world population attracts much attention, infertility in couples trying to conceive is quite common; it is estimated that in developed countries approximately 15% of such couples are infertile (1). The advent of assisted reproductive technologies (ART) has offered hope and a solution to many of these couples. In fact, since the birth of Louise Brown in 1978, it is estimated that some 2 million children have been conceived by ART. It is now recognized also that there are inherent risks associated with ART (2) that range from an increase in malformations (3) to low birth weight (4) and neurologic abnormalities (5) to an increased incidence of Angelman and Beckwith-Wiedemann syndromes because of loss of imprinting (6, 7). Although associations exist between these poor outcomes and ART, the mechanisms leading to them are poorly understood. One possibility is that the infertile population, per se, is predisposed to these Received February 11, 2006; revised and accepted May 25, 2006. Supported by a grant from the National Institutes of Health (HD 44575 to R.M.S.) as part of the National Cooperative Program on Female Health and Egg Quality and by a training grant from the National Institutes of Health (T32-HD40135) and a grant from the American Society for Reproductive Medicine (P.R.). Reprint requests: Paolo Rinaudo, Division of Reproductive Endocrinology and Infertility, University of California-San Francisco, 2356 Sutter St., San Francisco, CA 94115 (FAX 415-353-7744; E-mail: rinaudo@ obgyn.ucsf.edu).

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problems, independent of the technology used. Alternatively, the use of fertility drugs or the manipulation and culture of gametes and embryos in vitro could be causative. Embryo culture is often an intrinsic manipulation used in ART, and human preimplantation embryos are cultured for different lengths of time that range from 3 days that permit development to the 8-cell stage to 5– 6 days that support development to the blastocyst stage before embryo transfer. What is known from model systems is that embryo culture affects both embryo metabolism (8) and gene expression (9). Besides the composition of the medium used to culture embryos, oxygen concentration is likely to be a critical factor in the developing embryo’s response to the culture conditions. Although somatic cells typically are cultured in the presence of 20% oxygen, this oxygen concentration typically is not seen by most cells in mammals, but rather most cells, including human preimplantation embryos, experience an environment of reduced oxygen tension. For example, the oxygen concentration in the genital tract of the rabbit is approximately 5% (10), and today it is commonly accepted that a low oxygen concentration is present in the mammalian genital tract (11, 12). Numerous studies indicate that atmospheric oxygen concentration

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plays an important role in preimplantation embryo development in all species studied to date (11, 13), for example, slower rate of development in vitro and decreased cell number in blastocysts. Moreover, comet assays, which detect DNA damage, reveal that atmospheric oxygen compromises genomic integrity of mouse embryos that developed in vitro in the presence of either 5% or 20% oxygen (14). Such damage is likely the result of higher levels of reactive oxygen species in these embryos (15); reactive oxygen species can damage proteins, lipids, and DNA. Consistent with the aforementioned detrimental effect of high oxygen on preimplantation embryo development is that expression of a battery of protein biomarkers in embryos that develop in the presence of 5% oxygen more closely resembles that of in vivo– developed embryos, when compared with embryos that develop in the presence of 20% oxygen (16). Despite the known detrimental effects of atmospheric oxygen on preimplantation embryo development in these model systems, human preimplantation embryos routinely are cultured in the presence of 20% oxygen. Although there are reports that culture of human embryos in the presence of 20% oxygen for up to 3 days has no apparent detrimental effect on several clinical parameters (17), there are other reports that indicate the opposite (18, 19). Moreover, longer periods of culture in the presence of 20% oxygen are associated with reduced cell numbers in blastocysts and poorer morphology scores (17, 20) and abnormal preimplantation development (13). The effects of atmospheric oxygen on global patterns of gene expression have not been examined rigorously. We previously reported the effects of culture of 1-cell embryos to the blastocyst stage on global patterns of gene expression in blastocysts that developed in Whitten’s medium (WM) or KSOM ⫹ amino acids (KSOM/AA) in the presence of 5% oxygen (9). We have extended this study to examine the effect of culturing zygotes to the blastocyst stage in these media but in the presence of 20% oxygen. We report that global patterns of gene expression, when compared with embryos that developed in vivo, are per-

turbed to a greater extent after culture in 20% oxygen than when cultured in the presence of 5% oxygen. MATERIALS AND METHODS Collection of Preimplantation Mouse Embryos and RNA Extraction Mouse CF-1 x B6D2F1/J embryos were isolated from superovulated mice as previously described (9). In brief, CF-1 female mice were injected with 5 IU pregnant mare serum gonadotropin and 42– 46 hours later with 5 IU hCG; the females were then mated to B6D2F1/J males overnight. The following morning, zygotes were collected from the ampullae and cultured in either WM or KSOM/AA (9) to the blastocyst stage in either 5% CO2:5% O2:90% N2 or 5% CO2 in air at 37°C. Embryos collected from mice (approximately 18 per mouse) were pooled, and 20 embryos were randomly allocated and cultured in 20-␮L drops of the appropriate medium. Only cultures in which at least 85% of the embryos developed to the blastocyst stage were used for further analysis. In addition, only blastocysts that appeared morphologically normal and similar in appearance were used. All animal experiments were approved by the Institutional Animal Care and Use Committee. Cultures were initiated with more embryos when WM was used to compensate for the poorer development in WM compared with KSOM/AA. Blastocysts that developed in vivo were flushed from the uteri. Late-cavitating blastocysts of similar morphology from the control in vivo group were harvested at 96 hours after hCG. Pools of embryos were frozen in liquid nitrogen. RNA from each group of embryos was isolated, amplified, and hybridized to the Affymetrix chip (Affymetrix, Santa Clara, CA) at the same time to minimize experimental bias. Total RNA was extracted from pools of 80 embryos that developed in either WM or KSOM/AA in the presence of 20% O2 (120 ng of total RNA) with use of Trizol (Invitrogen, Carlsbad, CA) containing 2 ␮L of Pellet Paint (Novagen, Madison, WI) according to the manufacturer’s

TABLE 1 Effect of culture conditions on preimplantation development.

Treatment KSOM/AA 5% O2 KSOM/AA 20% O2 WM 5% O2 WM 20% O2

No. of zygotes

No. of 2-cell embryos

No. of blastocysts

Percent zygote to 2-cell

Percent 2-cell to blastocyst

Percent zygote to blastocyst

101 335 91 553

93 299 87 458

82 232 64 340

92.1a 89.3a 95.6a 82.8b

88.2a 77.6b 73.6b 74.2b

81.1b,f 69.2a,d 70.3d,e,f 61.4c,e

a, b, c, d, e, f

Values with different superscripts in each column differ significantly, P⬍.05. In each column the comparison applies to the four different culture conditions.

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TABLE 2 Effect of culture conditions on cell number. Treatment KSOM/AA 20% O2 WM 20% O2 KSOM/AA 5% O2 WM 5% O2 In vivo

No. of embryos (total)

No. of replicates

No. ICM cells (mean ⴞ SEM)

No. Total cells (mean ⴞ SEM)

59 46 25 27 23

5 5 3 3 4

11.2 ⫾ 0.4c 11.7 ⫾ 0.5c 23.5 ⫾ 0.8a 16.4 ⫾ 0.5b 12.6 ⫾ 0.6c

54.6 ⫾ 1.8c 52.0 ⫾ 2.5c 90.0 ⫾ 2.3a 73.6 ⫾ 2.1b 65.2 ⫾ 1.8b

a, b, c

Values with different superscripts in each column differ significantly, P⬍.05. In each column the comparison applies to the five different groups of embryos.

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instructions (Invitrogen). Total RNA was dissolved in 10 ␮L of sterile water and stored at ⫺80°C. Ribonucleic acid mass and size distribution were determined with use of the Agilent Bioanalyzer and RNA 6000 Nano LabChips (Agilent Technologies, Santa Clara, CA). Complementary DNA Preparation for Microarray Analysis Total RNA samples were submitted to the University of Pennsylvania Microarray Facility for target preparation and GeneChip hybridization. Total RNA yield was 78 – 213 ng per replicate pool. Seventy nanograms of total RNA was used for linear, two-round amplification by in vitro transcription (Affymetrix Small Sample Prep Technical Bulletin, www.affymetrix.com). Yield of complementary RNA (cRNA) after the first amplification was 1.2–7.4 ␮g, and 0.5 ␮g of each replicate was used as input template for the second amplification. Final yield of bio-

tinylated cRNA was 74 –115 ␮g, of which 15 ␮g per replicate was fragmented and hybridized to Affymetrix GeneChips. Samples of cRNA were hybridized to MOE430A GeneChips, then washed and stained on fluidics stations and scanned at 3 ␮m resolution according to the manufacturer’s instructions (GeneChip Analysis Technical Manual, www. affymetrix.com). Analysis of the Microarrays Microarray Analysis Suite 5.0 (MAS; Affymetrix) was used to quantify microarray signals with default analysis parameters and global scaling to target mean ⫽ 150. Quality control parameters for all samples were within the following ranges: scale factor 1.3–2.2, background 47–73, percent genes detected 37%– 43% on MOE430A, actin 3=/5= signal ratio 1.9 –2.7, and glyceraldehyde-3-phosphate dehydrogenase 3=/5= signal ratio 4.3– 6.5. The MAS

FIGURE 1 Confirmation of microarray data by real-time PCR. Three genes whose expression was either increased or decreased after culture in either WM or KSOM/AA in the presence of 20% oxygen were selected for analysis. The level of expression relative to embryos that developed in vivo (black bars) by either microarray analysis (A) or real-time PCR (B) was set as 1. Open bars, embryos cultured in KSOM/AA; red bars, embryos cultured in WM.

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metrics output was loaded into GeneSpring v5 (Agilent Technologies) with per-chip normalization to the 50th percentile and per-gene normalization to the median. A filtered list was created of all genes detected (MAS “P” call) in at least five of six replicates of the in vivo group. Independent analyses were applied to identify genes with statistically significant differences in any of the four culture conditions. The GeneSpring pairwise comparison (Welch t-test with analysis of variance [ANOVA], Pⱕ.05, Benjamini and Hochberg multiple-testing correction) was conducted between all the possible pairs combinations (in vivo, WM, KSOM/AA⬎). The GeneSpring multiclass analysis was applied to the entire sample set (Welch t-test with Welch ANOVA, Pⱕ.05, Benjamini and Hochberg multiple-testing correction). A one-way ANOVA for microarrays (lgsun.grc.nia.nih.gov/ANOVA/index.html, default parameters) also was conducted. A nonredundant list was compiled containing candidate genes called significantly different in at least one analysis.

FIGURE 3 Number of transcripts differentially expressed under different culture conditions. The data for embryos cultured in WM and KSOM/AA in the presence of 5% oxygen are from Rinaudo and Schultz (9). The number of genes either down- or up-regulated is the number that is statistically different from the control, that is, embryos that developed in vivo. The exact number of genes is as follow: WM 20% up-regulated (all genes: 725; more than twofold: 153; more than fivefold: 4); WM 20% down-regulated (434; 201; 13, respectively); KSOM/AA 20% up-regulated (175; 37; 4); KSOM/AA 20% down-regulated (179; 72; 5); WM 5% up-regulated (6; 2; 0); WM 5% downregulated (108; 40; 1); KSOM/AA 5% up-regulated (1; 1; 0); KSOM/AA 5% down-regulated (28; 16; 0).

Genes whose expression was altered after culture were imported to EASE to test for overrepresentation of gene ontology classes (9). As described previously (21), EASE is a program that provides statistical methods (reported as an EASE score) for discovering biological themes within gene lists using previously published annotation databases. All reported expression differences from genebased or annotation-based profiling were retested for statistical significance by multiclass ANOVA as appropriate.

FIGURE 2 Unsupervised clustering of the samples.

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Complementary DNA Preparation for Real-Time Polymerase Chain Reaction Analysis Reverse transcription and cDNA preparation were performed with a commercially available kit (iScript cDNA Synthesis Kit; Bio-Rad Laboratories, Hercules, CA) according to the manufacturer’s protocol. For each treatment group, reverse transcription was repeated three times with different sets of blastocysts.

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Real-time polymerase chain reaction (PCR) was performed with use of TaqMan Universal PCR Master Mix, Gene Expression Assays containing gene-specific primers and a TaqMan probe (Applied Biosystems, Foster City, CA), and 0.1 embryo equivalents of cDNA. The corresponding ABI TaqMan Assay-on-Demand probe/ primer sets used were Mm00498012_m1 (Ube2a), Mm00438084_m1 (Ccng1), Mm00599980_m1 (Dpf1), and Mm99999915_g1 (GAPDH). Three replicates were used for each real-time PCR reaction; a minus template served as control. Quantification was normalized to Gapdh. Data were analyzed within the log-linear phase of the amplifi1255

TABLE 3 EASE analysis of genes that are up- or down-regulated more than twofold in embryos cultured in WM–20% O2. EASE gene category

EASE score

Up-regulated Biosynthesis

3.85 ⫻ 10⫺2

Unigene clusters Mm.249342 Mm.288897 Mm.290960 Mm.274482 Mm.276294 Mm.486 Mm.2731 Mm.143738 Mm.18939 Mm.3117 Mm.4428

Lytic vacuole

7.12 ⫻ 10⫺4

Mm.29357 Mm.236553 Mm.2277 Mm.486 Mm.30071 Mm.271868

Microtubule cytoskeleton

4.41 ⫻ 10⫺2

GDP-dissociation inhibitor activity

4.55 ⫻ 10⫺2

Mm.259277 Mm.259568 Mm.286488 Mm.227274 Mm.5856 Mm.246436 Mm.31452 Mm.205830 Mm.30016

Down-regulated Heat shock protein activity

3.66 ⫻ 10⫺3

Mm.1777 Mm.239865 Mm.270681 Mm.22708

Gene description 7-dehydrocholesterol reductase Choline phosphotransferase 1 Cleft lip and palate associated transmembrane protein 1 Eukaryotic translation initiation factor 2C, 2 Ligatin Lysosomal membrane glycoprotein 2 Phosphatidylethanolamine Nmethyltransferase Phosphatidylinositol glycan, class O Phosphomannomutase 1 Pleckstrin homology-like domain, family A, member 1 Protein-kinase, interferon-inducible double stranded RNA dependent inhibitor, repressor of (P58 repressor) RIKEN cDNA 1300017C10 gene Cathepsin B Cathepsin H Lysosomal membrane glycoprotein 2 Lysosomal-associated protein transmembrane 4A Lysosomal-associated protein transmembrane 5 Palmitoyl-protein thioesterase 2 Scavenger receptor class B, member 2 Kinesin family member 22 Protein regulator of cytokinesis 1 RIKEN cDNA 6330412F12 gene RIKEN cDNA 6720463E02 gene T-box 20 Guanosine diphosphate (GDP) dissociation inhibitor 1 Rho GDP dissociation inhibitor (GDI) alpha Heat shock protein 1 (chaperonin) Heat shock protein 4 Heat shock protein 105 Serine (or cysteine) proteinase inhibitor, clade H, member 1

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TABLE 3 Continued. EASE gene category Mitochondrion

EASE score 8.76 ⫻ 10⫺3

Unigene clusters Mm.273175 Mm.2171 Mm.225505 Mm.3446 Mm.2475 Mm.1777 Mm.9925 Mm.253142 Mm.269649 Mm.241931 Mm.233117

Mm.33969 Mm.28626 Mm.286458 Mm.28756

Kinase activity

8.78 ⫻ 10⫺3

Mm.4222 Mm.3555 Mm.23335 Mm.10504 Mm.277373 Mm.225505 Mm.38390 Mm.3446 Mm.12616 Mm.20216 Mm.3810

Mm.8771 Mm.269649 Mm.4497 Mm.233117

Mm.27227 Mm.262330 Mm.28877

Gene description Aquaporin 8 ATPase inhibitor Choline kinase Deoxycytidine kinase Glutaryl-Coenzyme A dehydrogenase Heat shock protein 1 (chaperonin) Isocitrate dehydrogenase 1 (NADP⫹), soluble NADH dehydrogenase (ubiquinone) Fe-S protein 4 Phosphofructokinase, liver, B-type Protein phosphatase 1, catalytic subunit, beta isoform Pyrroline-5-carboxylate synthetase (glutamate gamma-semialdehyde synthetase) RIKEN cDNA 1200013F24 gene RIKEN cDNA 2410018G23 gene RIKEN cDNA 6430402H10 gene Solute carrier family 40 (ironregulated transporter), member 1 Triosephosphate isomerase Voltage-dependent anion channel 1 YME1-like 1 3-phosphoinositide dependent protein kinase-1 Calcium/calmodulin-dependent protein kinase I Choline kinase Copine III Deoxycytidine kinase DnaJ (Hsp40) homolog, subfamily C, member 3 Galactokinase 2 Phosphatidylinositol 3-kinase, C2 domain containing, alpha polypeptide Phosphatidylinositol-4-phosphate 5-kinase, type II, alpha Phosphofructokinase, liver, B-type PTK6 protein tyrosine kinase 6 Pyrroline-5-carboxylate synthetase (glutamate gamma-semialdehyde synthetase) RIKEN cDNA 5730469M10 gene Serine/threonine kinase 3 (Ste20, yeast homolog) UDP-glucose pyrophosphorylase 2

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TABLE 3 Continued. EASE gene category Nucleic acid binding

EASE score

Unigene clusters

9.63 ⫻ 10⫺3

Mm.10141 Mm.288669 Mm.29055 Mm.23178 Mm.20000 Mm.270346 Mm.27254 Mm.277680 Mm.2475 Mm.57223 Mm.155896 Mm.19806 Mm.256509 Mm.39999 Mm.227258 Mm.42196 Mm.271814 Mm.9901 Mm.154378 Mm.235580 Mm.235562 Mm.33969 Mm.46005 Mm.171469 Mm.1886 Mm.279736 Mm.45645 Mm.27330

Mm.4306 Mm.286449 Mm.216386 Mm.28877 Mm.23335 Mm.255890

Gene description Alpha thalassemia/mental retardation syndrome X-linked homolog (human) Basic leucine zipper and W2 domains 2 Chromobox homolog 1 (Drosophila HP1 beta) Cytoplasmic polyadenylation element binding protein 4 DEAH (Asp-Glu-Ala-His) box polypeptide 9 Developmentally and sexually retarded with transient immune abnormalities Ectonucleotide pyrophosphatase/ phosphodiesterase 1 Fusion, derived from t(12;16) malignant liposarcoma (human) Glutaryl-Coenzyme A dehydrogenase Helicase, lymphoid specific Heterogeneous nuclear ribonucleoprotein A2/B1 Histone deacetylase 2 Homeo box, msh-like 1 Inhibitor of growth family, member 3 Interleukin enhancer binding factor 2 Nuclear protein 95 Nuclear receptor co-repressor 1 Nucleobindin 2 Nucleolin Retinoblastoma-like 2 RIKEN cDNA 1110005A23 gene RIKEN cDNA 1200013F24 gene RIKEN cDNA 2600011C06 gene RIKEN cDNA 6820402O20 gene RNA and export factor binding protein 1 Splicing factor 3b, subunit 1 Splicing factor, arginine/serine-rich 1 (ASF/SF2) SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily e, member 1 Telomeric repeat binding factor 1 Transcription factor 3 U1 small nuclear ribonucleoprotein polypeptide A UDP-glucose pyrophosphorylase 2 YME1-like 1 (S. cerevisiae) Zinc finger protein of the cerebellum 3

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TABLE 3 Continued. EASE gene category mRNA metabolism

EASE score

Unigene clusters

2.92 ⫻ 10⫺2

Mm.23178 Mm.46005 Mm.1886 Mm.279736 Mm.45645

Gene description Cytoplasmic polyadenylation element binding protein 4 RIKEN cDNA 2600011C06 gene RNA and export factor binding protein 1 Splicing factor 3b, subunit 1 Splicing factor, arginine/serine-rich 1 (ASF/SF2)

mRNA, messenger RNA. Rinaudo. Gene expression in mouse embryos. Fertil Steril 2006.

cation curve obtained for each probe/primer with use of the comparative threshold cycle method. Differential Cell Staining in Blastocysts A dual nuclear staining method described by Thouas et al. (22) was performed with modifications to stain differentially inner cell mass (ICM) and trophectoderm cells of fully developed blastocysts. In brief, blastocysts were exposed to 1% Triton X-100 (Sigma-Aldrich Co., St. Louis, MO) in minimum essential medium (MEM; Invitrogen Corporation, Grand Island, NY) for 3–5 seconds, washed 3–5 times in MEM ⫹ polyvinylpyrrolidone (PVP; Sigma-Aldrich), and incubated in MEM⫹PVP containing 100 ␮g/mL propidium iodide (Sigma-Aldrich) for 30 seconds. The embryos were then washed three to five times in MEM⫹PVP and fixed overnight in 100% ethanol containing 25 ␮g/mL of bisbenzimide (Sigma-Aldrich). The embryos were mounted on a clean glass slide with use of glycerol and kept in a dark chamber until being observed under fluorescent light with a Leica microscope (model DMRB; Leica Microsystems AG, Wetzlar, Germany). The number of cells of the ICM (blue) and TE (red) were counted at ⫻400 magnification. The staining procedure was repeated three times per treatment group with different sets of blastocysts (Table 2).

Statistical Analyses Data analysis was performed by one-way ANOVA or ␹2 as appropriate. Cell number was compared with use of a mean separation procedure when ANOVA showed statistically significant F values with the Bonferroni (all-pairwise) multiple comparison test. Embryo development data were analyzed by ␹2 test. Results are reported as the mean values for each set of data ⫾ SEM. Fertility and Sterility姞

RESULTS AND DISCUSSION Effect of Embryo Culture in 20% O2 Versus 5% O2 on Embryo Development, Cell Number, and Morphology Before embarking on analyzing global patterns of gene expression in blastocysts that developed from the 1-cell stage in the presence of either 5% or 20% oxygen, we first confirmed the observation that 5% oxygen fosters better development in vitro (11, 13) (Table 1). Results of these experiments confirmed the beneficial effect of 5% oxygen on development of 1-cell embryos to the blastocyst stage and that KSOM/AA is a better medium than WM. Moreover, total cell numbers were increased after culture in either medium in the presence of 5% oxygen, and, as anticipated, embryos cultured in KSOM/AA contained the greatest number of cells (Table 2). Of note is that the embryos that developed in KSOM/AA in the presence of 5% oxygen contained more ICM cells and that the percentage of ICM cells was higher when compared with the other treatment groups. Moreover, embryos that developed in either medium in the presence of 20% oxygen contained fewer ICM cells. This latter observation may have clinical ramifications because ART-conceived children show a reduced weight after adjusting for maternal age and gestational age, even in singleton pregnancies (4). The decrease in total cell number, compared with embryos that developed in vivo, after culture in 20% oxygen was anticipated, given the known detrimental effects of 20% oxygen. The increase in total cell number, in particular the increase in the number of ICM cells, compared with embryos that developed in vivo, however, was unanticipated. Effect of Embryo Culture in 20% O2 Versus 5% O2 on Gene Expression Several studies have examined global patterns of gene expression in mouse embryos (9, 23–25), as well as in single human embryos (26), but none have systematically 1259

TABLE 4 EASE analysis of genes that are up- or down-regulated more than 2-fold in embryos cultured in KSOM/AA–20% O2. EASE score

Ease gene category Up-regulated Glycerophospholipid metabolism

GDP-dissociation inhibitor activity

Unigene clusters

1.67 ⫻ 10⫺3 Mm.288897 Mm.209300 Mm.143738 2.03 ⫻ 10⫺2 Mm.205830 Mm.30016

Down-regulated Mitochondrion

1.22 ⫻ 10⫺3 Mm.273175 Mm.148721 Mm.225505 Mm.548 Mm.253142 Mm.233117 Mm.33969 Mm.28626 Mm.286458 Mm.988 Mm.28756

Carboxylic acid metabolism

Mm.3555 1.97 ⫻ 10⫺2 Mm.2942 Mm.282096 Mm.267478 Mm.233117

Nuclear chromosome 2.60 ⫻ 10⫺2

Transporter activity

Mm.286458 Mm.18652 Mm.4222 Mm.29055 Mm.5001 Mm.27330

4.88 ⫻ 10⫺2 Mm.273175 Mm.148721 Mm.202257 Mm.38390 Mm.548 Mm.253142

Gene description Choline phosphotransferase 1 Phosphate cytidylyltransferase 1, choline, alpha isoform Phosphatidylinositol glycan, class O Guanosine diphosphate (GDP) dissociation inhibitor 1 Rho GDP dissociation inhibitor (GDI) alpha Aquaporin 8 ATP synthase, H⫹ transporting, mitochondrial F0 complex, subunit b, isoform 1 Choline kinase Cytochrome c oxidase, subunit VIc NADH dehydrogenase (ubiquinone) Fe-S protein 4 Pyrroline-5-carboxylate synthetase (glutamate gamma-semialdehyde synthetase) RIKEN cDNA 1200013F24 gene RIKEN cDNA 2410018G23 gene RIKEN cDNA 6430402H10 gene RIK ubiquinol cytochrome c reductase core protein 2 Solute carrier family 40 (iron-regulated transporter), member 1 Voltage-dependent anion channel 1 Asparagine synthetase Elongation of very long chain fatty acids (FEN1/ Elo2, SUR4/Elo3, yeast)-like 1 Fatty acid Coenzyme A ligase, long chain 6 Pyrroline-5-carboxylate synthetase (glutamate gamma-semialdehyde synthetase) RIKEN cDNA 6430402H10 gene Spermine synthase Triosephosphate isomerase Chromobox homolog 1 (Drosophila HP1 beta) DNA methyltransferase 3A SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily e, member 1 Aquaporin 8 ATP synthase, H⫹ transporting, mitochondrial F0 complex, subunit b, isoform 1 cDNA sequence BC019806 Copine III Cytochrome c oxidase, subunit VIc NADH dehydrogenase (ubiquinone) Fe-S protein 4

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TABLE 4 Continued. Ease gene category

EASE score

Unigene clusters Mm.42196 Mm.45994 Mm.988 Mm.14277 Mm.281804 Mm.28756 Mm.253984 Mm.5140 Mm.3555

Gene description Nuclear protein 95 RIKEN cDNA 9030418M05 gene RIK ubiquinol cytochrome c reductase core protein 2 Serum amyloid A3 Solute carrier family 15 (H⫹/peptide transporter), member 2 Solute carrier family 40 (iron-regulated transporter), member 1 Solute carrier family 6 (neurotransmitter transporter), member 14 Solute carrier family 7 (cationic amino acid transporter, y⫹ system), member 3 Voltage-dependent anion channel 1

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studied the effect of oxygen concentration on the global pattern of gene expression in the preimplantation embryo. Studies that have looked at the effect of oxygen concentration have focused only on expression of a very limited number of selected genes (e.g., Kind et al. [27]). Accordingly, we compared global patterns of gene expression in blastocysts that developed in vitro in the presence of 20% oxygen with use of the Affymetrix MOE430A chip, which contains approximately 22,000 transcripts, with results generated from our previous study in which embryos developed in the presence of 5% oxygen (9). Results from our previous studies using real-time PCR to confirm expression changes detected by microarrays (9, 24, 28) provide a high degree of confidence that changes in gene expression detected by the microarrays are real. Nevertheless, we conducted an additional analysis of a limited number of genes that displayed either a pronounced decrease or increase or a small increase to confirm the microarray results obtained in this study (Fig. 1). Results of this limited analysis indicated that for two of the genes an excellent correlation existed, whereas for the one that revealed a modest increase by microarray analysis, real-time PCR did not detect such an increase. To assess the power of the data sets to discriminate between the different developmental stages, we performed hierarchical clustering using the average distance metric to group the 22 sample data sets on the basis of the overall similarity of gene expression patterns (29) (Fig. 2). Save for one sample, the gene expression profile of embryos cultured in the presence of 5% oxygen more closely approximated that of embryos that developed in vivo when compared with those that developed in 20% oxygen, Fertility and Sterility姞

that is, low oxygen tension is more physiologic. The observation that the different culture media do not cluster together suggests that the relative influence of culture media on the global pattern of gene expression is small compared with the effect of oxygen concentration. It should be noted that although the overall transcriptomes were more similar than different, relatively small differences in gene expression at critical stages of development can have profound consequences. For example, experimentally manipulating levels of the transcription factor Oct4 by approximately 50% changed the fate of ES cells; for example, higher levels lead to differentiation into primitive endoderm and mesoderm, intermediate levels lead to pluripotent stem cells, and reduced levels result in trophectoderm (30). Results of a pair-wise comparison (Welch t-test with ANOVA, Pⱕ.05, Benjamini and Hochberg multiple-testing correction) conducted between the control group and each experimental group indicated a pronounced effect on perturbing the global pattern of gene expression after culture in 20% oxygen (Fig. 3), in which more genes were misregulated after culture in WM than in KSOM/AA. This result is consistent with KSOM/AA being a superior medium for culture of mouse preimplantation embryos (31) but also highlights the detrimental effect that 20% oxygen has on the global pattern of gene expression regardless of the culture medium. Gene lists for the genes that are misregulated are found in supplementary Tables S1 and S2 (available at www.fertstert.org). Analysis by EASE was conducted on the differentially expressed genes after culture in the presence of 20% oxygen in either medium to identify whether particular 1261

TABLE 5 EASE analysis of genes commonly mis-expressed following culture in 20% O2. Ease gene category

EASE score

Unigene clusters

Up-regulated GDP-dissociation inhibitor activity

1.42 ⫻ 10⫺2

Mm.205830

Glycerophospholipid biosynthesis Protein binding

2.02 ⫻ 10⫺2 4.92 ⫻ 10⫺2

Mm.30016 Mm.288897 Mm.143738 Mm.5183 Mm.1971 Mm.230844 Mm.87759 Mm.25568 Mm.271950 Mm.15105 Mm.4428

Down-regulated Mitochondrion

4.85 ⫻ 10⫺3

Mm.273175 Mm.225505 Mm.253142 Mm.233117

Mm.33969 Mm.28626 Mm.286458 Mm.28756

Pentose-phosphate shunt Cell growth and/or maintenance

3.51 ⫻ 10⫺2 3.60 ⫻ 10⫺2

Mm.3555 Mm.286458 Mm.4222 Mm.273175 Mm.277373 Mm.225505 Mm.29055 Mm.38390 Mm.292208 Mm.1019 Mm.42196 Mm.241931 Mm.74596 Mm.245746 Mm.33969 Mm.28626

Gene description Guanosine diphosphate (GDP) dissociation inhibitor 1 Rho GDP dissociation inhibitor (GDI) alpha Choline phosphotransferase 1 Phosphatidylinositol glycan, class O BTB and CNC homology 1 Calreticulin Coactivator-associated arginine methyltransferase 1 Enabled homolog (Drosophila) Expressed sequence A1118201 Golgi reassembly stacking protein 2 Inositol polyphosphate-5-phosphatase D Protein-kinase, interferon-inducible double stranded RNA dependent inhibitor, repressor of (P58 repressor) Aquaporin 8 Choline kinase NADH dehydrogenase (ubiquinone) Fe-S protein 4 Pyrroline-5-carboxylate synthetase (glutamate gamma-semialdehyde synthetase) RIKEN cDNA 1200013F24 gene RIKEN cDNA 2410018G23 gene RIKEN cDNA 6430402H10 gene Solute carrier family 40 (iron-regulated transporter), member 1 Voltage-dependent anion channel 1 RIKEN cDNA 6430402H10 gene Triosephosphate isomerase Aquaporin 8 Calcium/calmodulin-dependent protein kinase 1 Choline kinase Chromobox homolog 1 (Drosophila HP1 beta) Copine III Hepatoma-derived growth factor Interleukin 6 Nuclear protein 95 Protein phosphatase 1, catalytic subunit, beta isoform RAB10, member RAS oncogene family Radixin RIKEN cDNA 1200013F24 gene RIKEN cDNA 2410018G23 gene

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TABLE 5 Continued. Ease gene category

EASE score

Unigene clusters Mm.45994 Mm.28756 Mm.253984 Mm.5140 Mm.27330

Mm.5090 Mm.14455 Mm.3555

Gene description RIKEN cDNA 9030418M05 gene Solute carrier family 40 (iron-regulated transporter), member 1 Solute carrier family 6 (neurotransmitter transporter), member 14 Solute carrier family 7 (cationic amino acid transporter, y⫹ system), member 3 SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily e, member 1 Teratocarcinoma-derived growth factor Transforming growth factor, beta induced Voltage-dependent anion channel 1

Rinaudo. Gene expression in mouse embryos. Fertil Steril 2006.

biological processes or functions were preferentially affected (Tables 3 and 4); we have previously conducted such an analysis after culture in 5% oxygen (9). Of interest is that genes involved in cell growth and maintenance were misregulated after culture in the presence of 20% oxygen in either medium, but otherwise different biological processes were affected. Also of interest is the down-regulation of genes involved in gastrulation (e.g., Bmp4, Rnf2, Tdgf1, and Trim44) after culture in WM, which could compromise developmental competence of these blastocysts. Last, down-regulation of the de novo DNA methyltransferases Dnmt3a after culture in KSOM/AA could have implications for the observed increase in loss-of-imprinting Angelman and BeckwithWiedemann syndromes in humans (32) or other consequences that become manifest later in life. We also examined genes that are misexpressed more than twofold after culture in the presence of 20% oxygen (in both WM and KSOM/AA, Table 5). Overall 40.9% of the genes (147/359) differentially expressed in WM and 74.6% (147/197) differentially expressed in KSOM/AA are in common between the two groups. Oxygen-Regulated Genes Mammals have evolved complex circulatory systems to distribute the proper amount of oxygen to every cell in the body. In a similar fashion, individual cells have developed sophisticated mechanisms for oxygen sensing and gene regulation. In particular, in conditions of hypoxia, the HIF-1␣ pathway and genes with a hypoxia response element (33–37) are activated. In contrast, a high oxygen concentration triggers the Keap1-Nrf2 pathway and genes possessing an antioxidant response element (ARE) (38, 39). It Fertility and Sterility姞

should be stressed that a 5% oxygen concentration is not a hypoxic condition for the embryo (10) but rather a physiologic condition. Hypoxia-inducible factors (HIFs) are DNA-binding proteins composed of two subunits: ␣ and ␤. HIF-1␤ is constitutively expressed, whereas the HIF-1␣ subunit is stable only in cells cultured under low oxygen conditions; under high oxygen concentrations, HIF-1␣ is hydroxylated on specific proline residues that target the protein for degradation (40). Hypoxia-inducible factors modulate expression of several genes and regulate adaptive responses to alterations in O2. Many genes possess hypoxic response element (HRE) sites, which facilitate expression under low O2 conditions, and include glucose transporters (e.g., Slc2a1, Slca2a3) and glycolytic enzymes, genes involved in vascularization (e.g., vascular endothelial growth factor [Vegf], insulin-like growth factor-II [Igf2], and nitric oxide synthases [Nos]) and genes involved in erythropoiesis and iron metabolism (34, 36). Accordingly, we examined expression of genes involved in a hypoxia response or possessing an HRE (33). Fifty-five genes on the MOE 430 A chip met this classification, and 17 were expressed in the blastocysts (Table S3); see Table S4 for list of these genes. Noteworthy is that none of these were differentially expressed after culture in the presence of 5% oxygen in either KSOM or WM when compared with embryos that developed in vivo, which is consistent with a low oxygen concentration in the female reproductive tract. Hif-1␣ is expressed in the blastocyst, but its expression levels are not affected by either the oxygen concentration or culture medium used. This result is in accord with the work of Harvey et al. (41), who studied oxygen-regulated gene expression in 1263

bovine blastocysts. Slc2a1 expression is higher after culture in 2% oxygen (a true hypoxic condition) but does not change when embryos are cultured in 7% and 20% O2. We also found no effect of oxygen concentration on Slc2a1 expression. Antioxidant response elements (ARE) modulate expression of genes that confer protection against oxidative stress, and Nrf2 plays a central role in this process. Oxidative stress or electrophiles induce the release of NRF2 from the NRF2KEAP1 complex, resulting in nuclear translocation of NRF2, which binds to the ARE of phase II genes and stimulates their transcription (39). We identified 64 genes involved in the antioxidant response or possessing an antioxidant response element in the MOE430 A chip, of which 28 were expressed in the blastocyst (Table S3); see Table S5 for a list of these genes. Only six (Abcb6; Hnrph1; Map1lc3a; Pld3; Psmb4; Sqstm1) are abnormally regulated after culture in 20% oxygen. We anticipated a higher number of antioxidant genes to be abnormally regulated after culture in atmospheric oxygen. The significance of these findings is not apparent. In summary, results of experiments reported here provide additional support for culturing human embryos in the presence of 5% rather than 20% oxygen. The rationale for this suggestion is that 20% oxygen results in far greater perturbations in the global pattern of gene expression, regardless of whether the embryos were cultured in WM or KSOM/AA, than when the embryos are cultured in the presence of 5% oxygen, relative to the global pattern of gene expression observed in embryos that develop in vivo. Although this may be technically more difficult in the practice of ART, based on the mouse model system and work from other species, it seems a most reasonable suggestion. Acknowledgments: The authors thank John Eppig and Richard Tasca for helpful comments.

REFERENCES 1. Templeton A. Infertility— epidemiology, aetiology and effective management. Health Bull (Edinb) 1995;53:294 – 8. 2. Schultz RM, Williams CJ. The science of ART. Science 2002;296: 2188 –90. 3. Hansen M, Kurinczuk JJ, Bower C, Webb S. The risk of major birth defects after intracytoplasmic sperm injection and in vitro fertilization. N Engl J Med 2002;346:725–30. 4. Schieve LA, Meikle SF, Ferre C, Peterson H, Jeng G, Wilcox LS. Low and very low birth weight in infants conceived with use of assisted reproductive technology. N Engl J Med 2002;346:731–7. 5. Stromberg B, Dahlquist G, Ericson A, Finnstrom O, Koster M, Stjernqvist K. Neurological sequelae in children born after in-vitro fertilization: a population-based study. Lancet 2002;359:461–5. 6. DeBaun MR, Niemitz EL, Feinberg AP. Association of in vitro fertilization with Beckwith-Wideman syndrome and epigenetic alterations of LIT1 and H19. Am J Hum Genet 2003;72:156 – 60. 7. Cox GF, Burger L, Lip V, Mau U, Sperling K, Wu B. Intracytoplasmic sperm injection may increase the risk of imprinting defects. Am J Hum Genet 2002;71:162– 4. 8. Gardner DK. Changes in requirements and utilization of nutrients during mammalian preimplantation embryo development and their significance in embryo culture. Theriogenology 1998;49:83–102.

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9. Rinaudo P, Schultz RM. Effects of embryo culture on global pattern of gene expression in preimplantation mouse embryos. Reproduction 2004;128:301–11. 10. Mastroianni L Jr, Jones R. Oxygen tension within the rabbit fallopian tube. J Reprod Fertil 1965;147:99 –102. 11. Bavister B. Oxygen concentration and preimplantation development. Reprod Biomed Online 2004;9:484 – 6. 12. Fischer B, Bavister BD. Oxygen tension in the oviduct and uterus of rhesus monkeys, hamsters and rabbits. J Reprod Fertil 1993;99: 673–9. 13. Karagenc L, Sertkaya Z, Ciray N, Ulug U, Bahceci M. Impact of oxygen concentration on embryonic development of mouse zygotes. Reprod Biomed Online 2004;9:409 –17. 14. Takahashi M, Keicho K, Takahashi H, Ogawa H, Schultz RM, Okano A. Effect of oxidative stress on development and DNA damage in in-vitro cultured bovine embryos by Comet assay. Theriogenology 2000;54:137– 45. 15. Kitagawa Y, Suzuki K, Yoneda A, Watanabe T. Effects of oxygen concentration and antioxidants on the in vitro developmental ability, production of reactive oxygen species (ROS), and DNA fragmentation in porcine embryos. Theriogenology 2004;62:1186 –97. 16. Katz-Jaffe MG, Linck DW, Schoolcraft WB, Gardner DK. A proteomic analysis of mammalian preimplantation embryonic development. Reproduction 2005;130:899 –905. 17. Dumoulin JC, Meijers CJ, Bras M, Coonen E, Geraedts JP, Evers JL. Effect of oxygen concentration on human in-vitro fertilization and embryo culture. Hum Reprod 1999;14:465–9. 18. Catt JW, Henman M. Toxic effects of oxygen on human embryo development. Hum Reprod 2000;15 Suppl 2:199 –206. 19. Petersen A, Mikkelsen AL, Lindenberg S. The impact of oxygen tension on developmental competence of post-thaw human embryos. Acta Obstet Gynecol Scand 2005;84:1181– 4. 20. Gardner DK, Schoolcraft WB. Culture and transfer of human blastocysts. Curr Opin Obstet Gynecol 1999;11:307–11. 21. Hosack DA, Dennis G Jr, Sherman BT, Lane HC, Lempicki RA. Identifying biological themes within lists of genes with EASE. Genome Biol 2003;4:R70. 22. Thouas GA, Korfiatis NA, French AJ, Jones GM, Trounson AO. Simplified technique for differential staining of inner cell mass and trophectoderm cells of mouse and bovine blastocysts. Reprod Biomed Online 2001;3:25–9. 23. Hamatani T, Carter MG, Sharov AA, Ko MS. Dynamics of global gene expression changes during mouse preimplantation development. Dev Cell 2004;6:117–31. 24. Zeng F, Baldwin DA, Schultz RM. Transcript profiling during preimplantation mouse development. Dev Biol 2004;272:483–96. 25. Wang QT, Piotrowska K, Ciemerych MA, Milenkovic L, Scott MP, Davis RW, et al. A genome-wide study of gene activity reveals developmental signaling pathways in the preimplantation mouse embryo. Dev Cell 2004;6:133– 44. 26. Dobson AT, Raja R, Abeyta MJ, Taylor T, Shen S, Haqq C, et al. The unique transcriptome through day 3 of human preimplantation development. Hum Mol Genet 2004;13:1461–70. 27. Kind KL, Collett RA, Harvey AJ, Thompson JG. Oxygen-regulated expression of GLUT-1, GLUT-3, and VEGF in the mouse blastocyst. Mol Reprod Dev 2005;70:37– 44. 28. Pan H, O’Brien MJ, Wigglesworth K, Eppig JJ, Schultz RM. Transcript profiling during mouse oocyte development and the effect of gonadotropin priming and development in vitro. Dev Biol 2005;286: 493–506. 29. Eisen MB, Spellman PT, Brown PO, Botstein D. Cluster analysis and display of genome-wide expression patterns. Proc Natl Acad Sci U S A 1998;95:14863– 8. 30. Niwa H, Miyazaki J, Smith AG. Quantitative expression of Oct-3/4 defines differentiation, dedifferentiation or self-renewal of ES cells. Nat Genet 2000;24:372– 6.

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31. Summers MC, McGinnis LK, Lawitts JA, Raffin M, Biggers JD. IVF of mouse ova in a simplex optimized medium supplemented with amino acids. Hum Reprod 2000;15:1791– 801. 32. Gosden R, Trasler J, Lucifero D, Faddy M. Rare congenital disorders, imprinted genes, and assisted reproductive technology. Lancet 2003; 361:1975–7. 33. Ko MS, Kitchen JR, Wang X, Threat TA, Wang X, Hasegawa A, et al. Large-scale cDNA analysis reveals phased gene expression patterns during preimplantation mouse development. Development 2000;127:1737–49. 34. Bracken CP, Whitelaw ML, Peet DJ. The hypoxia-inducible factors: key transcriptional regulators of hypoxic responses. Cell Mol Life Sci 2003;60:1376 –93. 35. Iyer NV, Kotch LE, Agani F, Leung SW, Laughner E, Wenger RH, et al. Cellular and developmental control of O2 homeostasis by hypoxiainducible factor 1 alpha. Genes Dev 1998;12:149 – 62. 36. Wenger RH, Stiehl DP, Camenisch G. Integration of oxygen signaling at the consensus HRE. Sci STKE 2005;2005(306):re12.

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37. Semenza GL, Wang GL. A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation. Mol Cell Biol 1992;12:5447– 54. 38. Dinkova-Kostova AT, Holtzclaw WD, Cole RN, Itoh K, Wakabayashi N, Katoh Y, et al. Direct evidence that sulfhydryl groups of Keap1 are the sensors regulating induction of phase 2 enzymes that protect against carcinogens and oxidants. Proc Natl Acad Sci U S A 2002; 99:11908 –13. 39. Jaiswal AK. Nrf2 signaling in coordinated activation of antioxidant gene expression. Free Radic Biol Med 2004;36:1199 –207. 40. Jain S, Maltepe E, Lu MM, Simon C, Bradfield CA. Expression of ARNT, ARNT2, HIF1 alpha, HIF2 alpha and Ah receptor mRNAs in the developing mouse. Mech Dev 1998;73:117–23. 41. Harvey AJ, Kind KL, Pantaleon M, Armstrong DT, Thompson JG. Oxygen-regulated gene expression in bovine blastocysts. Biol Reprod 2004;71:1108 –19.

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TABLE S1 Genes misregulated after culture in WM. Common gene name Ccng1 Cd81 Mlf2 Eif2c2 Dhx16 Ccng1 Pdxk D10Ertd438e Hspb1 Ppp1r14a Rbm14 Rex3 Ccng1 Gdi1 Hist1h2bc 4930565N07Rik Ddit4I Laptm5 Scand1 Inpp5d Scarb2 Xrcc1 Pramel4 1810015H18Rik Guca1a Chpt1 Scrib Abhd4 Carm1 Gorasp2 BC038661 Pdxk Ren1 Timd2 6330412F12Rik Ccrn4I Fdx1 Enah 1110035H23Rik Npn3 Gna13 Itgb5 Ctsb Scarb1 Ppt2 Slc43a3 Bach1 Lamp2 Cdc25a Slc39a4

Genbank

UniGene

WM/control

NM_009831 NM_133655 BC003975 AW553784 BC009147 BG065754 BG063905 NM_030250 U03561 NM_026731 BB730281 NM_009052 BG085921 BC013758 NM_023422 BC007193 AF335325 BB218107 NM_020255 NM_010566 NM_007644 NM_009532 BG070047 AK009364 NM_008189 BC016251 BC006859 NM_134076 NM_021531 BC016455 AW494322 BG063905 NM_031192 BC025096 BG066220 AA798895 D43690 NM_010135 BB458178 BC011325 BG094302 BB543979 BC006656 BB138434 BC013462 NM_021398 NM_007520 NM_010685 NM_007658 BC023498

Mm.2103 Mm.806 Mm.29737 Mm.274482 Mm.298300 Mm.2103 Mm.206159 Mm.199964 Mm.13849 Mm.2343 Mm.183025 Mm.14768 Mm.2103 Mm.205830 Mm.261676 Mm.294006 Mm.250841 Mm.271868 Mm.297230 Mm.15105 Mm.259568 Mm.4347 Mm.271697 Mm.175989 Mm.16224 Mm.288897 Mm.25568 Mm.28771 Mm.230844 Mm.271950 Mm.105324 Mm.206159 Mm.220955 Mm.234654 Mm.5856 Mm.220953 Mm.1061 Mm.87759 Mm.28771 Mm.218639 Mm.193925 Mm.6424 Mm.236553 Mm.4603 Mm.259277 Mm.290729 Mm.5183 Mm.486 Mm.307103 Mm.276829

8.589 6.614 5.690 5.173 4.762 4.584 4.270 4.112 3.625 3.562 3.484 3.468 3.462 3.452 3.425 3.366 3.353 3.345 3.205 3.191 3.082 3.065 3.060 3.029 3.021 3.009 2.977 2.941 2.939 2.878 2.876 2.868 2.844 2.837 2.830 2.829 2.800 2.788 2.785 2.772 2.729 2.674 2.672 2.642 2.626 2.619 2.597 2.589 2.586 2.584

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TABLE S1 Continued. Common gene name Pemt Atp13a Uba52 6720463E02Rik 2310044H10Rik 4930438M06Rik Isyna1 Arhgdia Abhd5 Smyd2 Nt5c 4932431F02Rik BC011248 Grn Plec1 Bag3 Ncoa3 Calr Lgals8 Tnfaip1 Pem BC011248 Lgtn BC022641 Wbscr18 Lgtn C76566 5830484A20Rik 4833415N24Rik Tbx20 Pmm1 Tlk2; PKUalpha Dtx2 Ttll1 Adrm1 Ctsh Phlda1 Nr5a2 Mgat1 Poldip3 Bcap29 Cpsf1 Krtcap2 8030450I18Rik Clptm1 Pmm1 Supt5h Dpf2 BC023957 1110008P14Rik

Genbank

UniGene

WM/control

NM_008819 NM_133224 AU043383 AY029255 BC020179 BE311335 NM_023627 BC004732 AK007421 BC023119 NM_015807 BI408204 NM_027910 BB000455 AW123286 NM_013863 NM_008679 NM_007591 NM_018886 BC003906 BM210473 BB229004 BB238390 BI150732 NM_025362 BC025036 BG065702 BG072319 AK013460 AF306667 BC006809 AK014829 BB518874 BB251824 NM_019822 NM_007801 NM_009344 C80272 BB205495 BB534975 NM_007530 NM_053193 NM_025327 BB238427 NM_019649 BI739353 BC007132 NM_011262 BI412808 C79326

Mm.2731 Mm.186066 Mm.340728 Mm.246436 Mm.294759 Mm.21912 Mm.29357 Mm.30016 Mm.280254 Mm.156895 Mm.307174 Mm.25610 Mm.45101 Mm.1568 Mm.234912 Mm.84073 Mm.1011 Mm.1971 Mm.171186 Mm.10331 Mm.6923 Mm.45101 Mm.276294 Mm.28979 Mm.178012 Mm.276294 Mm.345718 Mm.335752 Mm.251639 Mm.31452 Mm.18939 Mm.4557 Mm.29343 Mm.235007 Mm.282084 Mm.2277 Mm.3117 Mm.16794 Mm.196933 Mm.23758 Mm.242379 Mm.45141 Mm.177991 Mm.135069 Mm.290960 Mm.18939 Mm.285906 Mm.2651 Mm.156565 Mm.27608

2.497 2.491 2.480 2.469 2.467 2.454 2.446 2.445 2.443 2.443 2.440 2.436 2.432 2.425 2.422 2.415 2.412 2.404 2.396 2.394 2.391 2.389 2.372 2.368 2.367 2.358 2.341 2.321 2.318 2.313 2.306 2.298 2.298 2.291 2.287 2.287 2.270 2.258 2.256 2.248 2.241 2.227 2.212 2.211 2.205 2.204 2.203 2.198 2.187 2.185

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TABLE S1 Continued. Common gene name Lrrc8 5430413I02Rik Dctn1 Kif1b Lrpap1 Grn 5430405G24Rik Enah G6pdx Akp5 Vps11 Kif22 LOC230761 Zmpste24 Ppp2r1a Csnk2a1 Sf3a1 Nr5a2 Pgrmc2 Taf6 Cad BC018222 Cd84 Ssr1 AI316828 Bzw1 2610019A05Rik Zfp148 Calr Gata6 Ncoa1 X83328 Laptm4a Pigo Zrf2; MIDA1 2310044D20Rik Csnk2a2 Lasp1 Gnas Vps11 Nosip Prkrir Myo1b Dhcr7 Trio 3100004P22Rik Stmn3 Prc1 Ubap2 Arhgap21

Genbank

UniGene

WM/control

BM942047 NM_019976 BF322032 AV104668 D00622 M86736 BM198273 BQ044016 NM_008062 NM_007433 AK004695 BB251322 BI409907 BM233793 BB192717 BB283759 BB031756 NM_030676 BQ175991 NM_009315 AK010453 BC026654 BM212728 AF395811 BB648848 AV144956 AK011451 X98096 AW324084 AF179425 NM_010881 NM_025275 BI695636 BB546713 AK013295 BC021428 BM212971 AV027151 NM_138658 AK004695 AK005700 AV328095 AI255256 NM_007856 BB794936 NM_133693 AV007850 BC005475 BC007179 BM213829

Mm.297949 Mm.23776 Mm.341049 Mm.252497 Mm.277661 Mm.1568 Mm.260282 Mm.87759 Mm.27210 Mm.195224 Mm.295013 Mm.286488 Mm.22616 Mm.34399 Mm.294138 Mm.298893 Mm.156914 Mm.16794 Mm.40321 Mm.248517 Mm.305535 Mm.31552 Mm.317380 Mm.138725 Mm.229654 Mm.261831 Mm.340911 Mm.256809 Mm.1971 Mm.329287 Mm.301039 Mm.291901 Mm.30071 Mm.143738 Mm.2467 Mm.272705 Mm.51136 Mm.200673 Mm.125770 Mm.295013 Mm.272139 Mm.4428 Mm.3390 Mm.249342 Mm.211229 Mm.306805 Mm.2319 Mm.227274 Mm.41864 Mm.28507

2.179 2.177 2.175 2.170 2.170 2.166 2.158 2.158 2.153 2.152 2.152 2.150 2.145 2.142 2.132 2.129 2.129 2.128 2.127 2.121 2.120 2.119 2.119 2.119 2.108 2.106 2.095 2.093 2.086 2.083 2.082 2.076 2.072 2.068 2.066 2.066 2.065 2.060 2.058 2.046 2.041 2.035 2.032 2.026 2.015 2.015 2.015 2.009 2.009 2.008

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TABLE S1 Continued. Common gene name Tnfsf5ip1 BC003332 Scarb1 Ube1x Bnip3l Rbm14 Tead4 Flot2 Ppp2r1a AW556797 Odc 3110038B19Rik Etf1 Rnf4 Sf3b4 1200010C09Rik L1cam Zfp296 Cherp Mapre2 Sec31I1 Calr Itgb5 Tacc2 Klf5 Snx6 Lrpap1 Lrpap1 Ezh1 D030034H08 0610040B21Rik Dazap1 0610042A05Rik Camk2d Orc2l Pigs Ris2 Exosc1 1700108L22Rik 1100001D10Rik Rhebl1 Scarb1 Gdap2 2610019I03Rik Thap4 8430421I07Rik Zfpm1 Surf4 Rbpms Llglh

Genbank

UniGene

WM/control

NM_134138 BB278670 NM_016741 NM_009457 NM_009761 AV213382 D87965 BB118974 BB397472 NM_134100 S64539 BC014817 C77379 AV045658 AU021081 AK004688 BB132473 NM_022409 BC020488 BC027056 BM222383 AW544960 NM_010580 BC004057 BI465857 BC025911 AV309553 D00622 NM_007970 BI083036 NM_029571 NM_133188 BB095413 AF059029 AW539841 BB309245 AF477481 BC024423 BC025528 BC003286 BC016521 BB224405 BC025070 NM_025639 BC013538 BB252881 AA014267 BF122782 BG069460 NM_008502

Mm.150701 Mm.100116 Mm.282242 Mm.1104 Mm.29820 Mm.183025 Mm.14774 Mm.3840 Mm.294138 Mm.287740 Mm.34102 Mm.29889 Mm.354729 Mm.21281 Mm.219671 Mm.149870 Mm.260568 Mm.349587 Mm.30136 Mm.132237 Mm.18634 Mm.1971 Mm.6424 Mm.302035 Mm.30262 Mm.28240 Mm.277661 Mm.277661 Mm.5027 Mm.331133 Mm.159965 Mm.148693 Mm.24365 Mm.255822 Mm.3411 Mm.295908 Mm.21873 Mm.289086 Mm.46782 Mm.275554 Mm.259708 Mm.4603 Mm.279228 Mm.23596 Mm.272356 Mm.275847 Mm.3105 Mm.2795 Mm.12436 Mm.285453

2.006 2.006 2.005 1.999 1.998 1.997 1.994 1.991 1.989 1.986 1.976 1.976 1.975 1.975 1.972 1.972 1.971 1.967 1.965 1.965 1.965 1.962 1.962 1.961 1.960 1.960 1.958 1.952 1.950 1.947 1.942 1.942 1.935 1.929 1.925 1.922 1.918 1.916 1.915 1.914 1.912 1.911 1.910 1.910 1.908 1.907 1.906 1.906 1.903 1.902

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TABLE S1 Continued. Common gene name Polrmt Ythdf1 Got2 9630002H22Rik Myo1c Txn2 Lats2 0610042I15Rik Atp6v1a1 Prc1 Tde1 Eif3s8 BC031407 Alad Cdc42ep5 Wbp11 Pla2g6 Laptm5 1300006C19Rik LOC216818 Ap2m1 AA960558 Add1 1810015H18Rik Crsp7 A330108F03Rik Slc9a3r1 1810031K17Rik Ctsd Solh Pigo Ddx52 2810406C15Rik 4632419K20Rik Gm542 Rfk Glg1 Prdx4 Gle1l Rec8L1 Tex261 Crk Eno1 AA409316 Ilf3 Tbrg4 Yif1 Rbm14 Tm7sf1 Rap2b

Genbank

UniGene

WM/control

AK003792 AV079675 NM_010325 BI251153 BQ176602 AV053127 AY015061 NM_019661 BI557654 BC005475 BM239368 AV235349 BC019178 BC018236 NM_021454 NM_021714 BC003487 U29539 AK018758 AU043470 C76671 NM_133942 BF140063 AK009364 AK017726 BB106270 BB805362 AK007667 NM_009983 BC022685 BB357373 BM247010 BC025460 BM214100 BG066456 AK008352 BG074127 NM_016764 AK016671 BB390936 AK013971 AF239673 NM_023119 BB021559 NM_010561 NM_134011 BC011117 NM_019869 BB726971 NM_028712

Mm.39001 Mm.30205 Mm.230169 Mm.272047 Mm.234502 Mm.3533 Mm.347899 Mm.294821 Mm.217787 Mm.227274 Mm.218473 Mm.22776 Mm.270044 Mm.6988 Mm.34268 Mm.141197 Mm.155620

1.902 1.894 1.892 1.891 1.889 1.885 1.885 1.884 1.884 1.881 1.879 1.878 1.875 1.875 1.873 1.872 1.869 1.868 1.864 1.862 1.862 1.860 1.857 1.854 1.851 1.848 1.845 1.841 1.837 1.836 1.835 1.832 1.831 1.830 1.830 1.826 1.826 1.820 1.820 1.819 1.815 1.810 1.809 1.809 1.806 1.806 1.804 1.804 1.801 1.797

Mm.296158 Mm.14707 Mm.18946 Mm.227474 Mm.289106 Mm.175989 Mm.353261 Mm.171514 Mm.27842 Mm.28193 Mm.231395 Mm.216072 Mm.143738 Mm.280544 Mm.257590 Mm.30254 Mm.8924 Mm.7013 Mm.276271 Mm.247542 Mm.275121 Mm.23149 Mm.28371 Mm.280125 Mm.70666 Mm.267178 Mm.20935 Mm.247761 Mm.44202 Mm.276338 Mm.313820 Mm.273288

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Gene expression in mouse embryos

Vol. 86, Suppl 3, October 2006

TABLE S1 Continued. Common gene name Itgb1 Wbp2 2810475A17Rik Cyct Atp2a2 Tfg Creg Tjp2 0610009K11Rik 1200015A19Rik Poldip3 Brd3 Cyp2s1 4930563C04Rik 1810030N24Rik Hist1h1c 1110011F09Rik Dab2 Lrpap1 Ovca2; 9030414M07Rik BC003331 Cdkap1 Xbp1 D7Ertd743e Btrc Riok3 2700083B06Rik E130309D02Rik Eif4ebp2 Fiz1 1110004D19Rik 1810009O10Rik Afar Ppih Ttk Nin Gata6 Tmem15 Akr1a4 Sf3b4 Crebbp Eno1 Prpf8 Nup133 Tpd52I2 Tex27 Exosc8 Jtb Mad2I2 Pld3

Genbank

UniGene

WM/control

BM120341 NM_016852 BC021337 NM_009989 BI248739 NM_019678 NM_011804 NM_011597 BC019516 BC019544 BI963573 BI414962 AK004699 BC016444 BG792484 NM_015786 BC016408 NM_023118 AI790446 NM_027136 BC003331 BB145140 AV051768 BB823331 AV339334 NM_024182 BC022614 BG069595 BB547478 AF126746 AK003410 BC027022 BB206121 AK014665 NM_009445 NM_008697 BM214048 BC026973 AK009462 BC024418 BG076163 BC004017 NM_138659 BC026845 BG069764 BG976649 C80158 BC008139 BC011282 NM_011116

Mm.263396 Mm.284792 Mm.28478 Mm.4872 Mm.227583 Mm.235108 Mm.459 Mm.104744 Mm.103413 Mm.288737 Mm.23758 Mm.28721 Mm.275188 Mm.340601 Mm.28071 Mm.193539 Mm.182563 Mm.240830 Mm.277661 Mm.41496 Mm.222093 Mm.196624 Mm.22718 Mm.43212 Mm.119717 Mm.28551 Mm.34109 Mm.138281 Mm.259516 Mm.38911 Mm.12746 Mm.341420 Mm.26463 Mm.196517 Mm.1904 Mm.244047 Mm.329287 Mm.26690 Mm.30085 Mm.219671 Mm.132238 Mm.70666 Mm.3757 Mm.267812 Mm.136648 Mm.220972 Mm.29253 Mm.13912 Mm.9648 Mm.6483

1.796 1.796 1.796 1.795 1.795 1.793 1.789 1.788 1.788 1.784 1.783 1.782 1.782 1.782 1.779 1.778 1.777 1.776 1.774 1.774 1.772 1.771 1.771 1.769 1.766 1.763 1.763 1.755 1.753 1.752 1.749 1.745 1.744 1.743 1.741 1.739 1.733 1.733 1.732 1.732 1.727 1.727 1.726 1.722 1.722 1.719 1.713 1.713 1.710 1.710

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TABLE S1 Continued. Common gene name Hras1 C230093N12Rik Scye1 Spna2 Slc11a2 D15Ertd81e Ctsz H2afx Mrps30 Ythdf2 2410001C21Rik Tm7sf1 Arfgap1 Usp1 Srpr Slc11a2 Acp2 Galk1 Cyb561 BC002230 Yif1 D3Ucla1 Polrmt AA589481 Thrap5 Eif2b4 Ide Pomt2 Rpn1 Taf10 Akr1a4 Esd Rbpms Lycat Cdkap1 Cttn 6530403A03Rik MrpI22 1700037H04Rik Nupl2 Srprb D8Ertd325e Nup50 4930521E07Rik Alg1 2410012H22Rik Cops7a Glul Ruvbl2 Acad9

Genbank

UniGene

WM/control

NM_008284 BC023470 NM_007926 AK011566 BG065264 C77953 NM_022325 NM_010436 AV095945 BC014797 BC004803 BB726971 BM196296 BQ033290 BC021839 BB772362 BB022890 NM_016905 BC006732 BC025577 BC011117 BF658806 BB739221 BB826899 BM238407 NM_010122 AK004972 AF246235 BB145729 NM_020024 AI627032 NM_016903 BG069460 BM237177 AV217570 BC011434 BE824567 BF018217 NM_026091 AB067574 BC003798 BC025071 NM_016714 BC027335 BC011281 AK010472 BG974128 U09114 NM_011304 AV235115

Mm.334313 Mm.4065 Mm.235137 Mm.204969 Mm.234608 Mm.291716 Mm.156919 Mm.245931 Mm.353262 Mm.23998 Mm.25157 Mm.313820 Mm.33765 Mm.280656 Mm.284688 Mm.234608 Mm.45570 Mm.2820 Mm.149403 Mm.224076 Mm.44202 Mm.29702 Mm.39001 Mm.24570 Mm.260089 Mm.29394 Mm.28366 Mm.232537 Mm.188544 Mm.285771 Mm.30085 Mm.38055 Mm.12436 Mm.329194 Mm.196624 Mm.205601 Mm.250783 Mm.259907 Mm.27711 Mm.45513 Mm.273053 Mm.178818 Mm.28379 Mm.60758 Mm.34581 Mm.141150 Mm.1444 Mm.210745 Mm.34410 Mm.260997

1.708 1.705 1.704 1.701 1.700 1.700 1.699 1.692 1.689 1.687 1.686 1.684 1.682 1.682 1.681 1.680 1.678 1.676 1.672 1.672 1.667 1.665 1.663 1.662 1.658 1.658 1.657 1.657 1.656 1.656 1.651 1.649 1.646 1.646 1.643 1.641 1.640 1.638 1.638 1.635 1.635 1.634 1.634 1.633 1.632 1.632 1.629 1.627 1.627 1.626

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Gene expression in mouse embryos

Vol. 86, Suppl 3, October 2006

TABLE S1 Continued. Common gene name Dnajb6 Rpn1 E030027H19Rik Map1lc3a AA536743 Cdc2I2 Smpd1 1810045K07Rik Skb1 Lig3 Shrm Sh3glb1 Ate1 Chaf1b Ap2b1 Leprotl1 Dusp11 Anapc2 BC031407 Zfp100 D5Wsu46e Llglh2 6430706D22Rik Rela Ppgb Gaa Tbl1x Pdcd6ip E430034L04Rik Cbll1 ORF19 Abcb6 Snapc2 Timm23 Dnpep Eno1 2310058J06Rik 1500016L11Rik Nipa Rpl37 Atp6v0b Dhps Slc35a4 Crip2 Psmd8 Acvr2b Nudt9 Prdx6 Ureb1 Dab2ip

Genbank

UniGene

WM/control

AK005680 AV308148 BM205949 BC010596 BC024679 NM_007661 NM_011421 BC022616 AF167573 BM248530 NM_015756 BC024362 NM_013799 BC013532 BG229812 AK003329 BB004080 AI036318 BC019178 NM_009541 BC017157 AY033650 BQ173888 NM_009045 NM_008906 BB357227 BB025726 C76364 BG069656 AF167441 BC025839 NM_023732 BB461550 NM_016897 BB407163 NM_023119 BC014727 BC012230 BI687848 AV110626 AV339131 AV033768 NM_026404 NM_024223 AK003436 NM_007397 AK004444 BB796358 BM248615 BM231046

Mm.290110 Mm.188544 Mm.27519 Mm.196239 Mm.243632 Mm.267410 Mm.4628 Mm.290353 Mm.196585 Mm.277136 Mm.46014 Mm.271775 Mm.216321 Mm.274222 Mm.39053 Mm.34212 Mm.24007 Mm.291624 Mm.270044 Mm.4340 Mm.61193 Mm.290450 Mm.259108 Mm.249966 Mm.7046 Mm.4793 Mm.258476 Mm.29816 Mm.290530 Mm.273270 Mm.296545 Mm.28663 Mm.28452 Mm.247093 Mm.24680 Mm.70666 Mm.227202 Mm.295670 Mm.29780 Mm.10474 Mm.3479 Mm.193086 Mm.273350 Mm.133825 Mm.273152 Mm.8940 Mm.241484 Mm.186185 Mm.27372 Mm.29629

1.624 1.623 1.622 1.621 1.616 1.616 1.612 1.611 1.610 1.609 1.608 1.608 1.604 1.604 1.603 1.603 1.600 1.598 1.597 1.593 1.593 1.592 1.590 1.590 1.590 1.589 1.587 1.587 1.586 1.585 1.585 1.584 1.584 1.583 1.579 1.578 1.573 1.572 1.571 1.571 1.570 1.568 1.568 1.564 1.564 1.564 1.563 1.562 1.561 1.560

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TABLE S1 Continued. Common gene name Syngr1 ORF6 Flot2 D19Ertd721e Sgta Snap29 Zfp106 Atp2a2 Ube2d3 Acate3 BC005682 Btrc Nfatc3 Psat1 Emb Gab1 Mad2l1bp Dnpep Ddx27 Gulo 0610039A15Rik Ctdsp2 Ccnf Alg3 Pisd Tpm1 Pole Wdfy1 2410016F01Rik 1810055E12Rik Rnf14 Smyd5 HnrpII Adrbk1 1700024N20Rik Bmpr1a Lypla2 Anapc7 Dctn4 Rab40c Kif5b Slc9a3r1 Rrm2 Zfp294 Pa2g4 Nedd4I Fip1I1 1110031B06Rik Odag Copz1

Genbank

UniGene

WM/control

NM_009303 NM_013859 NM_008028 AU041099 BC003836 AK007065 BC025424 NM_009722 BG070759 NM_022816 NM_033562 AF110396 BF124648 BC004827 BF163003 BC007483 AK011037 BB553721 BC024730 BC019856 BC004641 BB294133 NM_007634 BI144423 BB504983 BM232388 NM_011132 BC025226 AB030190 AK004643 NM_020012 BF160651 BC006805 AF333028 AV072100 BM248248 NM_011942 NM_019805 BE648494 BC027008 NM_008448 BB805362 BF119714 BM231649 AW536189 BB759157 BM199874 BC023182 BC019449 BC002246

Mm.230301 Mm.2310 Mm.130227 Mm.27839 Mm.30068 Mm.271992 Mm.195877 Mm.227583 Mm.49884 Mm.352763 Mm.28131 Mm.119717 Mm.276000 Mm.289936 Mm.274926 Mm.277409 Mm.272024 Mm.24680 Mm.295031 Mm.26207 Mm.275989 Mm.165096 Mm.77695 Mm.24950 Mm.30245 Mm.121878 Mm.35061 Mm.293273 Mm.249986 Mm.26148 Mm.228903 Mm.219946 Mm.197483 Mm.254144 Mm.277501 Mm.237825 Mm.34302 Mm.37341 Mm.272801 Mm.328872 Mm.223744 Mm.27842 Mm.99 Mm.249005 Mm.4742 Mm.98668 Mm.272468 Mm.26680 Mm.178424 Mm.29473

1.560 1.558 1.557 1.548 1.546 1.542 1.541 1.541 1.541 1.540 1.537 1.536 1.536 1.534 1.533 1.533 1.530 1.529 1.529 1.527 1.526 1.526 1.526 1.523 1.523 1.521 1.521 1.521 1.520 1.520 1.520 1.519 1.519 1.518 1.518 1.518 1.518 1.517 1.517 1.514 1.514 1.511 1.511 1.510 1.509 1.507 1.505 1.505 1.504 1.504

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Vol. 86, Suppl 3, October 2006

TABLE S1 Continued. Common gene name Apg7I 2310051D06Rik 5730444A13Rik Pdir 9830109N13Rik 5730445F03Rik Myef2 Hsd3b7 Ddb1 Abt1 Trim28 2610318K02Rik Supv3I1 Psmd3 Slc5a11 2210016F16Rik Pou2f1 Zfp289 Ywhab Aptx Apg16l Rpn1 D11Ertd18e 4633402N23Rik Ubap1 Cdk2ap1 Pi4k2a 6330412F12Rik Smarcad1 Dctn1 Dnpep Phc2 AI194308 3110048E14Rik Rai12 Pmm2 Nfyc Rpn1 Cstf1 1110014C03Rik Tial1 Sf4 Mrps17 Mrps34 Ctsz Arhgap1 LOC224833 Siat7d Poldip2 Zfp62

Genbank

UniGene

WM/control

⬎AW549826 AK009926 BC021497 BC009151 BC028835 BG963358 AF483504 NM_133943 NM_015735 AB021860 NM_011588 NM_026519 AI452098 NM_009439 AK008219 BI415578 NM_011137 NM_023854 NM_018753 AK005286 AK005181 BB519934 AK003278 BQ033255 AV132698 AK004852 BB208212 BB730849 BM055692 NM_007835 BB396885 BB334118 NM_138752 NM_133750 AK011130 AK002858 BC020117 NM_133933 NM_024199 BI409239 BM122619 BC027188 AK003008 NM_023260 NM_022325 BC006592 BC006605 AK007601 BB797282 BM230481

Mm.275332 Mm.24603 Mm.38816 Mm.71015 Mm.281189 Mm.33797 Mm.299755 Mm.157103 Mm.289915 Mm.292094 Mm.15701 Mm.220942 Mm.235898 Mm.12194 Mm.211838 Mm.296610 Mm.245261 Mm.43636 Mm.34319 Mm.269799 Mm.272972 Mm.188544 Mm.131618 Mm.29694 Mm.289795 Mm.332693 Mm.117037 Mm.5856 Mm.99113 Mm.6919 Mm.24680 Mm.259103 Mm.235700 Mm.247535 Mm.13430 Mm.9699 Mm.27220 Mm.188544 Mm.26944 Mm.342568 Mm.242072 Mm.17665 Mm.249809 Mm.328851 Mm.156919 Mm.22413 Mm.100154 Mm.27446 Mm.197493 Mm.295906

1.502 1.500 1.500 1.499 1.498 1.498 1.495 1.494 1.490 1.487 1.484 1.484 1.483 1.482 1.481 1.481 1.480 1.478 1.478 1.476 1.475 1.470 1.468 1.466 1.464 1.464 1.462 1.461 1.461 1.460 1.460 1.458 1.457 1.457 1.456 1.454 1.453 1.453 1.453 1.451 1.450 1.447 1.447 1.447 1.446 1.446 1.444 1.444 1.443 1.443

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TABLE S1 Continued. Common gene name Tnrc11 Xpot Gns 2310076K21Rik Lias 2610030J16Rik Gorasp2; p59; GRS2; GOLPH2; GRASP55; 0610011A07Rik; 2410043M02Rik; 5730520M13Rik; 9430094F20Rik Cox8a Hdh G630055P03Rik Mast2 0610041B22Rik Tfip11 Ppp1r10 Defcr9 Arhgap17 Plekhe1 Pxk D130005A03Rik Tbl3 Hnrpu Cdk5rap1 9130404D14Rik 4432417N03Rik Nfatc3 Fdft1 Ptprs Canx Carm1 Triobp Vrk3 Jak2 Zfp403 Bcl2l1 Mrps2 Etf1 4933435E07Rik Arf4 2610204K03Rik Sdbcag84 Ppfibp2 Dgat1 Tomm22 Zdhhc4 2610031L17Rik Ppp3ca

Genbank

UniGene

WM/control

AF071310 AK003432 BB445684 BC025125 NM_024471 BB396486 AK010664

Mm.20873 Mm.25042 Mm.207683 Mm.277533 Mm.195776 Mm.27170 Mm.23836

1.440 1.440 1.438 1.438 1.437 1.436 1.434

NM_007750 L23312 BG172318 NM_008641 BC016203 NM_018783 BC004771 U03065 AV351061 BC024670 BC016131 AW212577 BC019504 BF228203 NM_025876 BF166604 BC024698 U28807 NM_010191 D28530 AK017254 AV166218 BC003984 NM_133945 AU023352 AB064543 BM228788 AV031454 C77379 AK004549 BI653265 BM118985 BB556862 NM_008905 BC003717 AK008133 AK007572 BC014869 BQ173889

Mm.14022 Mm.209071 Mm.334775 Mm.9287 Mm.41463 Mm.172947 Mm.29385 Mm.290583 Mm.193021 Mm.24115 Mm.29515 Mm.320059 Mm.100353 Mm.2115 Mm.289427 Mm.219676 Mm.4206 Mm.276000 Mm.343538 Mm.258771 Mm.248827 Mm.230844 Mm.123714 Mm.28816 Mm.275839 Mm.254056 Mm.238213 Mm.294951 Mm.354729 Mm.250359 Mm.281836 Mm.173119 Mm.141276 Mm.2817 Mm.22633 Mm.246435 Mm.261606 Mm.292001 Mm.331389

1.434 1.432 1.431 1.430 1.430 1.430 1.429 1.428 1.428 1.428 1.427 1.426 1.425 1.423 1.423 1.420 1.419 1.419 1.418 1.416 1.415 1.414 1.412 1.412 1.412 1.405 1.405 1.405 1.403 1.403 1.402 1.402 1.402 1.401 1.401 1.401 1.400 1.399 1.399

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1265.e11 Rinaudo et al.

Gene expression in mouse embryos

Vol. 86, Suppl 3, October 2006

TABLE S1 Continued. Common gene name 3830408P06Rik Psmd4 Thoc3 Pex19 Pou6f1 Elp3 Miz1 Crb3 D17Wsu104e AW011752 Mgea6 Zfp598 Rbm14 Donson Rdbp Lzf Scpep1 2810405O22Rik Eif4b 6330441O12Rik 1500019G21Rik Gnpda2 Man2b1 Hras1 Gm169 AA407809 Kpnb3 Rad51ap1 5031436O03Rik 1300012G16Rik Pr1 1110004D19Rik 2410006F12Rik 2210016L21Rik Bap1 D10Ertd641e Eif3s7 Ptpn1 5730408C10Rik Xpo4 Phgdh Aldh3a2 Ebp D13Wsu50e 2410104I19Rik Sqstm1 Akt1 Zfp289 Ube3c Kctd10

Genbank

UniGene

WM/control

BC005522 AB029146 BE335845 BC019767 AK009674 BB172662 BG065828 BC024462 NM_080837 BQ177215 BB703735 BF385956 NM_009032 BQ174742 NM_138580 BC006914 AK014680 AK005112 BI152195 BM120228 NM_024172 AK015527 BC005430 BC011083 BC027306 NM_030724 BG089635 BC003738 AV287497 BB018522 BC024613 AK003410 BC011155 BG076998 AK009033 AU015124 NM_018749 BC010191 AK017523 NM_020506 L21027 NM_007437 NM_007898 NM_138596 NM_133691 BM232298 NM_009652 BB317953 AV273537 BC006935

Mm.29631 Mm.2261 Mm.292487 Mm.247764 Mm.28825 Mm.29719 Mm.6370 Mm.260076 Mm.294870 Mm.276386 Mm.244118 Mm.219581 Mm.276338 Mm.328698 Mm.279907 Mm.27792 Mm.34126 Mm.27794 Mm.290022 Mm.259498 Mm.6803 Mm.33830 Mm.4219 Mm.334313 Mm.296088 Mm.280895 Mm.221452 Mm.204634 Mm.229761 Mm.100065 Mm.24750 Mm.12746 Mm.259270 Mm.292672 Mm.3779 Mm.21793 Mm.3955 Mm.277916 Mm.261818 Mm.202747 Mm.324382 Mm.145091 Mm.27183 Mm.52583 Mm.29965 Mm.40828 Mm.6645 Mm.43636 Mm.137746 Mm.268504

1.399 1.397 1.392 1.391 1.390 1.389 1.389 1.386 1.385 1.384 1.380 1.380 1.380 1.379 1.377 1.377 1.375 1.375 1.374 1.371 1.370 1.369 1.368 1.365 1.364 1.363 1.363 1.363 1.363 1.363 1.361 1.359 1.358 1.358 1.354 1.353 1.353 1.350 1.348 1.345 1.344 1.344 1.344 1.343 1.342 1.340 1.338 1.337 1.337 1.337

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1265.e12

TABLE S1 Continued. Common gene name Ugalt2 Bag1 Glce 2310079P12Rik Serac1 Syngr2 D10Bwg1364e Ankfy1 AU024582 Xab2 Kctd5 Cdc34 MrpI37 Arhgef16 Copa 2610524G07Rik Calm3 Cryab Bcap37 Tfb2m Mrpl55 D10Ertd641e Psme3 Pcbp2 Fzd3 Polg Pex3 Fnbp4 1600029D21Rik 2410018G20Rik Gch Bmyc 2310004K06Rik 9130221H12Rik Dnajd1 1110032N12Rik Mybl2 Nmt1 Wdr5 Pcsk7 0610041B22Rik Ddx56 Bysl 1300006N24Rik Mrpl10 Psmd11 2310011J03Rik Eps8l2 Kpna3 Zfp239

Genbank

UniGene

WM/control

NM_016752 NM_009736 AK003758 BI152383 BB785152 BC004829 BC005632 NM_009671 BM248309 NM_026156 BF577853 BI794243 BC011065 BB235768 BQ175820 BI082843 AU079142 NM_009964 BB791424 AV003728 BM209870 BC025117 U60330 NM_011042 AU043193 BM934958 AK012827 AK013152 BC022950 AK010544 NM_008102 AK012810 AK007430 BG808297 NM_025384 BB396413 NM_008652 BC016526 AV095579 NM_008794 BC016203 BC018291 NM_016859 AK020979 BC016219 BI677127 AK020401 NM_133191 NM_008466 NM_008616

Mm.4593 Mm.688 Mm.24411 Mm.2947 Mm.5548 Mm.300628 Mm.29802 Mm.10313 Mm.206371 Mm.23739 Mm.28171 Mm.21981 Mm.29517 Mm.38481 Mm.30041 Mm.315430 Mm.288630 Mm.178 Mm.36241 Mm.293529 Mm.282694 Mm.21793 Mm.288477 Mm.236513 Mm.243722 Mm.3616 Mm.282711 Mm.207895 Mm.29959 Mm.22351 Mm.10651 Mm.330057 Mm.240668 Mm.348028 Mm.248046 Mm.27039 Mm.4594 Mm.10265 Mm.28265 Mm.3255 Mm.41463 Mm.29810 Mm.27291 Mm.196137 Mm.208946 Mm.260539 Mm.19031 Mm.27451 Mm.25548 Mm.347577

1.336 1.333 1.330 1.330 1.329 1.329 1.329 1.329 1.329 1.327 1.325 1.325 1.324 1.324 1.321 1.321 1.320 1.319 1.318 1.317 1.315 1.315 1.314 1.314 1.312 1.304 1.303 1.301 1.301 1.300 1.297 1.296 1.295 1.295 1.295 1.295 1.293 1.292 1.291 1.289 1.285 1.280 1.279 1.278 1.275 1.274 1.273 1.268 1.265 1.265

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Vol. 86, Suppl 3, October 2006

TABLE S1 Continued. Common gene name Pard6b Diap1 0610043B10Rik 5730436H21Rik Spg4 Smc1I1 2610208E05Rik Smfn Atp6v0b Mod1 Ncdn Mrpl2 Prkx Ufd1I 2610016C23Rik 1110007L15Rik 4933439C20Rik Zswim1 D15Ertd785e Atp6v1a1 Hadhb Sca2 Anapc4 1700012G19Rik Psen1 C130052l12Rik 1110032N12Rik Cyhr1 Nif3l1 Al114950; RIC-8 Txnl1 Bcap37 Plekhf1 Golga2 Rnpepl1 Srpk1 Ubxd1 2310079F23Rik Hdlbp Mrpl4 Rab11b Ppp2r1a Bat1a Nubp1 Shmt2 Cd2bp2 Fuca AA959742 Al317395 Scoc

Genbank

UniGene

WM/control

BE953582 BM120370 BI660196 NM_134139 AK007793 NM_019710 AA250510 BC003445 NM_033617 NM_008615 BC017126 NM_025302 C78183 AK012543 AK016786 BC019557 AA673371 BC025184 BM244537 NM_007508 BG866501 AW544490 BC024870 W59405 BQ030850 BC026562 BC019480 BB323901 NM_022988 BC005633 BI416051 AV212294 BC002120 NM_133852 BB540667 AK015754 NM_024432 BB095491 NM_133808 NM_023167 BE986863 BC006606 BB461609 NM_011955 BB758291 NM_027353 NM_024243 NM_133807 BC018406 NM_134118

Mm.292834 Mm.195916 Mm.27114 Mm.29627 Mm.19804 Mm.26412 Mm.1182 Mm.21911 Mm.207052 Mm.148155 Mm.220885 Mm.29183 Mm.106185 Mm.237594 Mm.262151 Mm.270137 Mm.30245 Mm.161149 Mm.143167 Mm.217787 Mm.291463 Mm.260900 Mm.272568 Mm.28541 Mm.998 Mm.30099 Mm.180622 Mm.346039 Mm.143166 Mm.34315 Mm.19169 Mm.36241 Mm.333798 Mm.106376 Mm.200971 Mm.15252 Mm.28000 Mm.98522 Mm.30012 Mm.155033 Mm.35727 Mm.294138 Mm.126043 Mm.29037 Mm.29890 Mm.28050 Mm.290126 Mm.172720 Mm.55513 Mm.219245

1.264 1.264 1.260 1.259 1.256 1.250 1.247 1.245 1.245 1.244 1.244 1.242 1.240 1.239 1.232 1.231 1.226 1.225 1.225 1.222 1.222 1.221 1.221 1.219 1.214 1.209 1.204 1.202 1.202 1.200 1.197 1.197 1.196 1.190 1.183 1.182 1.182 1.180 1.179 1.177 1.172 1.167 1.161 1.160 1.160 1.158 1.157 1.155 1.155 1.154

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TABLE S1 Continued. Common gene name Cdipt Nrd1 Npdc1 Slc39a3 Smarca4 Ars2 Dhx30 Mrps7 Mrps18b Polr2e Pgam1 Dmap1 2510001I10Rik Fdft1 AF233884 BC006909 Fadd Suv39h1 D3Ertd330e D030060M11Rik Rhog Eif3s9 2310073E15Rik Bin3 Stip1 Igf2bp1 Zdhhc16 D15Ertd747e D15Wsu75e Asb6 Arhgap1 6130401J04Rik Copg2 Ldh1 Hspca Fasn Sfrs2 Pvt1 Bing4 D3Ertd789e Igsf4a Tada2l B4galt6 Spin Chic1 Eif5a Zap3 5230400G24Rik Tmsb10

Genbank

UniGene

WM/control

BC021473 BC026832 NM_008721 AV369681 BG064918 BC019117 NM_133347 AK012225 BC021752 NM_025554 BI407347 AF438610 AK010881 BB028312 AB077991 BC006909 BC021400 AF193862 BG070740 BC025490 BC004794 BG923834 AK010864 NM_021328 NM_016737 NM_009951 NM_023740 BB236260 NM_134095 NM_133346 BB825698 BB796558 NM_017478 BF135641 NM_010699 C77287 AF127033 AF250133 NM_011222 NM_020603 BB410567 NM_018770 BB440612 BI685536 AV100078 Y11896 BC024899 AB033168 BC016597 AV148480

Mm.28219 Mm.274950 Mm.1131 Mm.5353 Mm.286593 Mm.27932 Mm.276305 Mm.193040 Mm.29484 Mm.18579 Mm.315962 Mm.29142 Mm.29432 Mm.343538 Mm.86482 Mm.44183 Mm.5126 Mm.9244 Mm.278922 Mm.32648 Mm.302013 Mm.21671 Mm.20848 Mm.24186 Mm.258633 Mm.294769 Mm.20387 Mm.28597 Mm.213261 Mm.27656 Mm.22413 Mm.122430 Mm.39896 Mm.284163 Mm.29324 Mm.1843 Mm.236443 Mm.21841 Mm.4608 Mm.2437 Mm.40931 Mm.307293 Mm.45159 Mm.26364 Mm.42193 Mm.42223 Mm.196607 Mm.153183 Mm.139176 Mm.346305

1.153 1.153 1.151 1.149 1.149 1.149 1.144 1.143 1.138 1.137 1.137 1.135 1.124 1.114 1.110 1.106 1.099 1.096 1.093 1.085 1.081 1.056 1.043 1.041 1.028 1.024 1.022 1.015 1.004 0.984 0.974 0.966 0.956 0.944 0.934 0.932 0.923 0.914 0.897 0.895 0.885 0.871 0.870 0.868 0.867 0.845 0.827 0.809 0.806 0.802

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1265.e15 Rinaudo et al.

Gene expression in mouse embryos

Vol. 86, Suppl 3, October 2006

TABLE S1 Continued. Common gene name Aldh6a1 2310009N05Rik Actr2 Cks1 1600014E20Rik 8430437G11Rik Bscl2 Cklfsf6 Tcl1 1110032D12Rik Clic4 Cnn3 Rbm8 Narg1 5730421E18Rik Psmb4 D19Wsu12e Sesn1 Atp11b Lck C530050O22Rik Ap3s1 Kcmf1 Zfp36I1 Psph 2610007A16Rik 2610028H07Rik 4833421E05Rik C630029K18Rik Ssfa1 Hmgb1 Gng10 3110006P09Rik Rps21 Emp2 Ube2d3 1110008H02Rik Zfp292 Rab10 Pafah1b3 9430077C05Rik Ssb Atp5b Mfn1 Smpdl3b Dtr 1110032D12Rik Fem1b Blvra

Genbank

UniGene

WM/control

NM_134042 AK009256 AK014859 NM_016904 AK005451 BC007160 BI080136 BC027248 NM_009337 AA409396 BB398988 BB833102 NM_025875 NM_053089 BG070516 AV212146 BI663634 AV016566 BC026741 BC011474 BG064945 NM_009681 NM_019715 M58566 NM_133900 BC027244 BC006738 AU016407 BQ176091 BC026755 NM_010439 NM_025277 AW536850 AW046420 AV151252 BE571790 BB427315 AW988981 BB315561 AW107754 NM_008776 BM250266 AK017822 NM_016774 C79511 NM_133888 L07264 AW824211 BM232562 AK010847

Mm.247510 Mm.29247 Mm.259045 Mm.3049 Mm.22 Mm.254845 Mm.345134 Mm.28858 Mm.18154 Mm.325307 Mm.257765 Mm.22171 Mm.261972 Mm.275281 Mm.283342 Mm.368 Mm.267131 Mm.276226 Mm.239416 Mm.293753 Mm.260601 Mm.301471 Mm.29194 Mm.18571 Mm.271784 Mm.307315 Mm.335449 Mm.297155 Mm.278578 Mm.299312 Mm.207047 Mm.41780 Mm.3035 Mm.258724 Mm.289669 Mm.246009 Mm.49884 Mm.28311 Mm.38193 Mm.74596 Mm.597 Mm.34309 Mm.10508 Mm.238973 Mm.290414 Mm.287187 Mm.289681 Mm.325307 Mm.24069 Mm.22028

0.799 0.796 0.795 0.793 0.782 0.780 0.780 0.777 0.776 0.774 0.771 0.770 0.769 0.767 0.766 0.764 0.755 0.752 0.750 0.747 0.745 0.745 0.743 0.735 0.735 0.734 0.734 0.732 0.728 0.727 0.727 0.725 0.724 0.724 0.722 0.722 0.722 0.717 0.712 0.708 0.707 0.706 0.706 0.705 0.697 0.695 0.693 0.691 0.690 0.690

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TABLE S1 Continued. Common gene name Ppap2a Acsl5 Rnf2 4932441K18 P4ha2 Ltb4dh Ywhag Gosr1 Akap8 H2afz Gadd45g Snapc3 Slc35f5 Rsu1 Prss11 Dsg2 BC017133 Tera Rps8 Myl6 Ppid Tsix Renbp Ndufs4 Erh Asb13 6230416J20Rik 1110060D06Rik Acp6 Ccni Lasp1 Gstk1 A030012M09Rik Phb Anxa7 Eif4a1 Cnbp1 Dctn6 H2-BI 1110067D22Rik 4933425K02Rik Ncl S100a10 2810013E07Rik Sptlc2 Morf4l1 Ralb Tes 2700094K13Rik 2610103J23Rik

Genbank

UniGene

WM/control

NM_008903 AK006541 BC020122 BG069603 NM_011031 BC014865 BM949577 BC008542 BG069776 AV003424 AK007410 AW537061 BB752003 NM_009105 NM_019564 C79957 BC017133 NM_019643 BQ127746 BI108818 BC011499 BG806300 NM_023132 AV219958 BB071632 NM_080857 BB827546 AK004325 AB030038 BC003290 BB105164 AK002661 BB151391 NM_008831 BC008997 BF320852 NM_013493 NM_011722 NM_008199 BC019131 AK015318 AF318184 NM_009112 BB206299 BC003227 BE197350 BB465250 BC010465 BI408855 BM118725

Mm.317186 Mm.292056 Mm.31512 Mm.319839 Mm.3705 Mm.34497 Mm.233813 Mm.20931 Mm.328945 Mm.916 Mm.281298 Mm.271985 Mm.28654 Mm.905 Mm.30156 Mm.345891 Mm.287208 Mm.18637 Mm.205037 Mm.337074 Mm.295252 Mm.346558 Mm.236969 Mm.253142 Mm.21952 Mm.253061 Mm.74730 Mm.319964 Mm.101368 Mm.250419 Mm.271967 Mm.267014 Mm.21539 Mm.263862 Mm.280231 Mm.328549 Mm.290251 Mm.150373 Mm.34289 Mm.76694 Mm.85000 Mm.154378 Mm.1 Mm.246713 Mm.565 Mm.277480 Mm.27832 Mm.271829 Mm.259293 Mm.288982

0.689 0.689 0.689 0.687 0.687 0.686 0.683 0.681 0.681 0.678 0.677 0.676 0.671 0.669 0.667 0.666 0.666 0.665 0.664 0.664 0.663 0.663 0.663 0.661 0.660 0.657 0.656 0.655 0.655 0.654 0.653 0.650 0.650 0.650 0.648 0.646 0.645 0.645 0.642 0.641 0.641 0.640 0.637 0.633 0.633 0.632 0.631 0.631 0.628 0.627

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Vol. 86, Suppl 3, October 2006

TABLE S1 Continued. Common gene name Gcnt2 Satb1 Nup88 Nnt 2410195B05Rik Car4 1300007B12Rik Dsg2 Sfrs3 Yy1 Rpl13a Rps6 Large 2410018G23Rik Denr Zfp238 Msh6 Morf4l1 Cox5b 3110013H01Rik Snag1 Ywhaq Iars Morf4l1 2410018G23Rik Hmgb3 Kdt1 2810468K05Rik Hnrph1 A030012M09Rik Acp5 2500002K03Rik Slc25a5 Luc7l2 Gmnn 2610510D13Rik Eef1e1 Gyk Tmpo D14Ertd209e; 2310032K15Rik Pla2g10 Yes Spag7 Ddx3y Lgals3 Thoc3 Rpl13a Usp7 Pip5k2a

Genbank

UniGene

WM/control

BM236768 AV172776 BE951220 BC008518 BG069700 NM_007607 NM_020588 C79957 NM_013663 BM236739 BF659630 C81225 NM_010687 BE200117 NM_026603 NM_013915 BM250164 AU042749 AA960638 AK014046 NM_130796 AV024540 BE915338 BB767552 BE200117 NM_008253 U13371 BB272466 BB164501 BB818670 AK008391 BC016218 C81442 BG070818 NM_020567 BC024454 NM_025380 NM_008194 AW547481 AK009576 AF166097 NM_009535 BB239907 AA210261 C79043 X16834 BC019603 BF146301 AW548146 AK012196

Mm.26734 Mm.4381 Mm.288962 Mm.195803 Mm.137966 Mm.1641 Mm.18230 Mm.345891 Mm.6787 Mm.3868 Mm.180458 Mm.292504 Mm.324371 Mm.28626 Mm.28549 Mm.27962 Mm.18210 Mm.277480 Mm.180182 Mm.307700 Mm.33721 Mm.289630 Mm.21118 Mm.310288 Mm.28626 Mm.336087 Mm.1314 Mm.28277 Mm.21740 Mm.21539 Mm.46354 Mm.29181 Mm.658 Mm.276133 Mm.12239 Mm.316306 Mm.36683 Mm.246682 Mm.159684 Mm.5750 Mm.4214 Mm.301516 Mm.21569 Mm.302938 Mm.352798 Mm.248615 Mm.292487 Mm.180458 Mm.295330 Mm.8771

0.623 0.620 0.620 0.617 0.613 0.612 0.611 0.611 0.610 0.608 0.606 0.603 0.603 0.603 0.602 0.598 0.597 0.597 0.596 0.595 0.595 0.594 0.592 0.590 0.589 0.587 0.585 0.584 0.583 0.582 0.580 0.580 0.580 0.580 0.580 0.572 0.571 0.571 0.571 0.571 0.571 0.570 0.569 0.568 0.568 0.567 0.566 0.565 0.565 0.565

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TABLE S1 Continued. Common gene name Ppp1cb 4933421H10Rik Prpf4b Rpl15 Ddx21 Grcc9 Trim44 4631427C17Rik Sfpq BC003885 D15Ertd366e D4Ertd89e Arl3 G430041M01Rik Lcp1 B4galt6 E2f5 Prss11 Pdgfra Map17 Slc35a2 Nupl1 Nsbp1 Smarca3 5430433L24Rik Cct3 Satb1 Shmt1 1110001P04Rik Hsp105 Actc1 BC005537 Map17 Pygb 2810405K02Rik Slc7a7 Rpl14 2610209F03Rik Capg Slc38a4 AA408868 Ahcyl1 Rps6 Set 3110043J09Rik Rb1cc1 Idb3 B3gnt5 H2afy Nol5a

Genbank

UniGene

WM/control

BB816770 BB409331 AV114845 BM213176 NM_019553 AA153477 BB115834 BG072404 BF224766 BC003885 AV114522 C77858 NM_019718 BG069073 NM_008879 BG066773 BC003220 BB559067 AW537708 BC013542 BB228713 BB100348 NM_016710 BB206482 AV293164 AL024092 BG092481 BC026055 BI692575 D67017 NM_009608 BB655799 AA396586 AW547988 AI836168 NM_011405 NM_025974 AU016334 NM_007599 AK003626 NM_030612 BB831090 AA103697 BF134272 BC010306 AB050017 NM_008321 NM_054052 AF171080 BF660256

Mm.241931 Mm.99961 Mm.10027 Mm.2050 Mm.25264 Mm.261906 Mm.103583 Mm.210899 Mm.257276 Mm.312227 Mm.33207 Mm.27184 Mm.22085 Mm.196598 Mm.153911 Mm.26364 Mm.153415 Mm.30156 Mm.221403 Mm.30181 Mm.214976 Mm.258051 Mm.298443 Mm.209650 Mm.23846 Mm.256034 Mm.4381 Mm.355690 Mm.28869 Mm.270681 Mm.686 Mm.266668 Mm.30181 Mm.222584 Mm.41868 Mm.142455 Mm.289810 Mm.219668 Mm.18626 Mm.250980 Mm.247272 Mm.220328 Mm.292504 Mm.28805 Mm.128411 Mm.293811 Mm.110 Mm.33935 Mm.283802 Mm.29363

0.564 0.563 0.563 0.562 0.561 0.558 0.558 0.557 0.556 0.556 0.553 0.551 0.551 0.550 0.549 0.547 0.547 0.546 0.546 0.543 0.539 0.538 0.536 0.536 0.535 0.533 0.533 0.532 0.531 0.531 0.530 0.530 0.527 0.526 0.526 0.526 0.524 0.523 0.522 0.522 0.521 0.520 0.520 0.519 0.515 0.513 0.513 0.512 0.511 0.511

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Vol. 86, Suppl 3, October 2006

TABLE S1 Continued. Common gene name Map4k4 Vps54 Shmt1 Sfrs3 1110006I15Rik Hspa14 Stk31 Hspd1 2510006D16Rik Sms Vdac1 1200003C05Rik Arhgap5 Bzw2 Hnrpa2b1 Atpi Serpinh1 Birc6 Luc7l2 Tnpo1 1190002N15Rik Dstn Idh1 Hells; LSH; Lysh; PASG; YFK8 Pip5k2a Yme1I1 1110006I15Rik BC019806 2310057G13Rik Dnajc3 Tars 1200013I08Rik Nid1 5031439A09Rik Sumo3 Sfrs1 Reps1 2410018G23Rik Hcapg-pending Lpl Hdgf Snrp70 2410018G23Rik Cnbp Fusip1 5830417C01Rik Sfrs1 Cldn3 Cycs Sh3md2

Genbank

UniGene

WM/control

BQ175905 NM_139061 BC026055 BB492363 BB117756 NM_015765 AK021186 AI648003 BC024696 NM_009214 AV020390 BC002238 AV006000 BM932775 C88150 NM_007512 BI220012 NM_007566 BI076494 BI696984 BB500104 NM_019771 AI788952 NM_008234 BC011097 BB826168 BB477208 AV094699 AK009957 AV024539 AK010256 BI738010 NM_010917 BM241735 NM_019929 BG071935 NM_009048 AV337733 BB702347 NM_008509 NM_008231 BC002169 BB815513 AV299745 AF060490 BB245100 BF147037 AW611462 AK002732 BB072090

Mm.19073 Mm.170103 Mm.355690 Mm.6787 Mm.30020 Mm.89341 Mm.128054 Mm.1777 Mm.293096 Mm.18652 Mm.3555 Mm.278477 Mm.35059 Mm.288669 Mm.155896 Mm.2171 Mm.22708 Mm.290908 Mm.276133 Mm.173286 Mm.258746 Mm.28919 Mm.9925 Mm.57223 Mm.8771 Mm.23335 Mm.251890 Mm.202257 Mm.245537 Mm.12616 Mm.286061 Mm.26696 Mm.4691 Mm.6766 Mm.24433 Mm.45645 Mm.4479 Mm.28626 Mm.32012 Mm.1514 Mm.292208 Mm.216386 Mm.28626 Mm.7335 Mm.10229 Mm.346691 Mm.45645 Mm.158662 Mm.35389 Mm.27949

0.511 0.510 0.507 0.506 0.505 0.504 0.500 0.500 0.500 0.500 0.499 0.497 0.497 0.496 0.495 0.494 0.494 0.488 0.487 0.487 0.485 0.481 0.478 0.476 0.476 0.475 0.474 0.472 0.471 0.471 0.470 0.470 0.469 0.468 0.468 0.468 0.466 0.466 0.465 0.462 0.462 0.461 0.460 0.460 0.458 0.457 0.454 0.451 0.451 0.451

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TABLE S1 Continued. Common gene name Ncl Rpl22 Etv3 1200009K13Rik Pycs Ptprk Ywhab D14Wsu89e Hnrpa2b1 Akr1b3 Tcfcp2l2 Ywhab Ywhab Sh3d1B Cul4a Hmgcr Chchd3 4930470H18Rik; 3110012M05Rik Mapbpip Nutf2 Pdzk1; Pdzd1; mPDZK1; D3Ertd537e Ugp2 Tcf3 Soat1 Hibadh Ncl Tmsb10 Hibadh Hdac2 Marcks 1110064P04Rik Ndufs4 Rab14 Chd4 Ncor1 Sf3b1 Nucb2 Fus Ppp1cb Hsp105 Rab10 Ugp2 Slc16a1 Cebpa Marcks Snap23 Trip11 Tmsb10

Genbank

UniGene

WM/control

BC005460 BC021344 BI456953 BC006030 BF148128 AW741711 AV021552 AA410148 AU019883 NM_009658 BC013080 AV021552 BQ175227 AI326108 BC024113 BB123978 BC021941 BC017628

Mm.154378 Mm.307846 Mm.34510 Mm.240490 Mm.233117 Mm.332303 Mm.34319 Mm.288693 Mm.155896 Mm.451 Mm.263068 Mm.34319 Mm.34319 Mm.139128 Mm.212861 Mm.316652 Mm.21501 Mm.63425

0.449 0.448 0.447 0.446 0.445 0.445 0.445 0.443 0.442 0.437 0.435 0.434 0.434 0.434 0.433 0.433 0.433 0.432

NM_031248 BC003955 AK006269

Mm.41680 Mm.306812 Mm.28015

0.431 0.431 0.430

AW146314 NM_009332 NM_009230 BC003914 BF118393 NM_025284 BB805796 NM_008229 AW546141 BM120737 NM_010887 BQ031435 BC005710 AW555798 NM_031179 NM_016773 BE985138 AW823525 BI499717 BF465974 AW146314 NM_009196 BC011118 BB454540 BM220554 AV013785 BB096368

Mm.28877 Mm.286449 Mm.28099 Mm.286458 Mm.117581 Mm.3532 Mm.286458 Mm.19806 Mm.30059 Mm.13148 Mm.253142 Mm.198264 Mm.183257 Mm.271814 Mm.279736 Mm.9901 Mm.277680 Mm.241931 Mm.270681 Mm.74596 Mm.28877 Mm.9086 Mm.35567 Mm.30059 Mm.245715 Mm.355302 Mm.346305

0.426 0.425 0.425 0.424 0.423 0.420 0.417 0.417 0.416 0.416 0.416 0.415 0.414 0.414 0.412 0.412 0.411 0.410 0.409 0.408 0.408 0.405 0.404 0.403 0.403 0.402 0.398

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Vol. 86, Suppl 3, October 2006

TABLE S1 Continued. Common gene name

Genbank

UniGene

WM/control

1200013F24Rik Tiparp C030034I22Rik Asns Cpeb4 1110005A23Rik S100a10 Pgk1 Ewsh Mcl1 Mcl1 Terf1 9030416H16Rik Vdac1 2310042E22Rik Fzd7 Dhx9 Camk1 Hrsp12; HR12; HRP12 Akr1b3 1110005A23Rik Plekhh1 Klf9 Lgals4 H19 F2r Cbx1 Iif2 Cpne3 Refbp1 Pik3c2a Tm4sf3 Dusp6 Tm4sf3 Ephx2 Tpi Ddx5 Hspa1a 0610009H04Rik 1700009P03Rik C330018J07Rik 6820402O20Rik Arid5b Mtm1 Dsg2 Gcdh Spred1 Camk1 3110003A17Rik Manba

NM_025822 BB762264 C77501 BC005552 NM_026252 AV084012 AV295650 BB411302 BB699868 AV318494 AV274748 NM_009352 BG067505 AV036172 AV010984 AK010239 U91922 NM_133926 AK005016 AV127085 NM_025364 BC006045 AV354744 BC021632 NM_023123 AV024285 BB224832 BC024718 BB398005 NM_011568 AI746434 BC025461 NM_026268 C76990 NM_007940 NM_009415 AV114523 M12573 AY082613 AW544305 AV234245 BB308157 BB699910 NM_019926 BG242290 NM_008097 AV295157 NM_133926 AK013984 NM_027288

Mm.33969 Mm.246398 Mm.327235 Mm.2942 Mm.23178 Mm.10278 Mm.1 Mm.316355 Mm.142822 Mm.1639 Mm.1639 Mm.4306 Mm.278974 Mm.3555 Mm.310250 Mm.297906 Mm.20000 Mm.277373 Mm.2607 Mm.339309 Mm.235562 Mm.268317 Mm.19788 Mm.210336 Mm.14802 Mm.24816 Mm.29055 Mm.227258 Mm.38390 Mm.1886 Mm.3810 Mm.22270 Mm.1791 Mm.22270 Mm.15295 Mm.4222 Mm.220038 Mm.275405 Mm.272687 Mm.291542 Mm.212606 Mm.171469 Mm.270346 Mm.274981 Mm.345891 Mm.2475 Mm.245890 Mm.277373 Mm.276041 Mm.280536

0.396 0.394 0.394 0.394 0.393 0.392 0.391 0.391 0.388 0.388 0.388 0.387 0.386 0.386 0.385 0.385 0.382 0.381 0.381 0.380 0.379 0.377 0.375 0.374 0.373 0.369 0.362 0.361 0.361 0.360 0.357 0.356 0.355 0.355 0.351 0.350 0.349 0.349 0.349 0.348 0.347 0.347 0.346 0.346 0.341 0.339 0.336 0.336 0.335 0.335

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TABLE S1 Continued. Common gene name Eva Slc6a14 Uhrf1 Dck Nnt Hnrph2 2600011C06Rik Rcn Ube2a C920006C10Rik; mKIAA0143 Hspa1a Pfkp Rpl31 Pfkl 2900024C23Rik Smarce1 Chka Hnrpa2b1 Mep1b Galk2 Entpd1 Enpp1 Stk3 Usp25 Tgfbi Pycs 5033405D03Rik PdpkI Ing3 Ndrg1 Rbl2 Ndrg1 B3gnt5 Rdx Asns Ugp2 Tgfbi Lrrfip1 Tm4sf3 Blnk 1300002F13Rik Bmp4 Il6 Slc40a1 Commd1 Enpp1 Plscr1 Atrx Ndr1 Tfpi

Genbank

UniGene

WM/control

BC015076 NM_020049 NM_010931 BB030204 BB205930 NM_019868 AV253813 NM_009037 NM_019668 NM_133766 M12573 AV304625 NM_053257 BE914497 BM114165 AK018493 NM_013490 NM_016806 NM_008586 BB771515 BE307478 C76301 AY058922 NM_013918 BB533460 BB251523 BB559878 NM_011062 BB020556 AI790290 AA138720 NM_008681 BM214359 NM_009041 AV212753 AV370025 BB532080 AV301584 C76990 AF068182 NM_133753 NM_007554 NM_031168 BC003438 AB076722 AF339910 BF319989 BM230515 AV309418 AF004833

Mm.33240 Mm.253984 Mm.42196 Mm.3446 Mm.3842 Mm.315909 Mm.46005 Mm.4876 Mm.172835 Mm.260647 Mm.275405 Mm.108076 Mm.298467 Mm.269649 Mm.277897 Mm.27330 Mm.225505 Mm.155896 Mm.2682 Mm.20216 Mm.2824 Mm.27254 Mm.262330 Mm.40986 Mm.14455 Mm.233117 Mm.19352 Mm.10504 Mm.39999 Mm.30837 Mm.235580 Mm.30837 Mm.33935 Mm.245746 Mm.2942 Mm.28877 Mm.14455 Mm.45039 Mm.22270 Mm.9749 Mm.249333 Mm.6813 Mm.1019 Mm.28756 Mm.29542 Mm.27254 Mm.14627 Mm.10141 Mm.4063 Mm.124316

0.334 0.333 0.324 0.324 0.323 0.322 0.311 0.310 0.308 0.306 0.304 0.301 0.298 0.297 0.293 0.292 0.292 0.292 0.289 0.288 0.288 0.285 0.282 0.282 0.276 0.273 0.273 0.271 0.268 0.261 0.260 0.259 0.256 0.255 0.251 0.246 0.245 0.244 0.243 0.242 0.241 0.237 0.235 0.234 0.233 0.232 0.231 0.228 0.222 0.222

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Vol. 86, Suppl 3, October 2006

TABLE S1 Continued. Common gene name Aqp8 Saa3 Hspa4 2900024C23Rik Msx1 5730469M10Rik Slc7a3 Tdgf1 Mitf Zic3 Ptk6 Gsta2 9030418M05Rik Socs3 Nupr1

Genbank

UniGene

WM/control

NM_007474 NM_011315 AW909503 BM114165 BC016426 AK017688 NM_007515 AV294613 BB763517 BB732077 NM_009184 NM_008182 NM_133681 BB241535 NM_019738

Mm.273175 Mm.14277 Mm.239865 Mm.277897 Mm.256509 Mm.27227 Mm.5140 Mm.5090 Mm.100641 Mm.255890 Mm.4497 Mm.197422 Mm.45994 Mm.3468 Mm.18742

0.214 0.210 0.183 0.180 0.177 0.175 0.174 0.172 0.159 0.157 0.142 0.111 0.099 0.044 0.034

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TABLE S2 Genes misregulated after culture in KSOM/AA. Common gene name Ccng1 Cd81 Atp13a 4930565N07Rik Trio Ndufab1 Abhd4 9130011B11Rik Inpp5d Gorasp2 Mlf2 Clptm1 Rap2b Ndrg4 Ubc Enah Ppt2 Grn Arhgdia Orc2l Tulp4 Slc38a1 Add1 Calr 4930563C04Rik Dp1 Prkrir Dazap1 0610042A05Rik Dctn1 BC022641 Ccng1 Arhgap21 BC011248 Mbp 9630002H22Rik Pigs Ubap2 Sumo3 Enc1 Tlk2; PKUalpha E030024M05Rik Sycp1 Cdc25a Crk Cdc42ep5 Shmt1 Zrf2; MIDA1 Dpf2 Klf5

Genbank

UniGene

KAA/control

NM_009831 NM_133655 NM_133224 BC007193 BB794936 AK010307 NM_134076 BG068678 NM_010566 BC016455 BC003975 NM_019649 BB645629 AV006122 AW551908 BQ044016 BC013462 BB000455 BC004732 AW539841 NM_054040 NM_134086 BF140063 NM_007591 BC016444 AV054377 AV328095 NM_133188 BB095413 BF322032 BI150732 BG065754 BM213829 NM_027910 L07508 BI251153 BB309245 BC007179 NM_019929 BM120053 AK014829 BC025220 AV275615 NM_007658 AF239673 NM_021454 BC026055 AK013295 NM_011262 BI465857

Mm.2103 Mm.806 Mm.186066 Mm.294006 Mm.211229 Mm.347976 Mm.28771 Mm.251196 Mm.15105 Mm.271950 Mm.29737 Mm.290960 Mm.273288 Mm.29846 Mm.331 Mm.87759 Mm.259277 Mm.1568 Mm.30016 Mm.3411 Mm.28251 Mm.103568 Mm.289106 Mm.1971 Mm.340601 Mm.280075 Mm.4428 Mm.148693 Mm.24365 Mm.341049 Mm.28979 Mm.2103 Mm.28507 Mm.45101 Mm.252063 Mm.272047 Mm.295908 Mm.41864 Mm.24433 Mm.241073 Mm.4557 Mm.5675 Mm.292306 Mm.307103 Mm.280125 Mm.34268 Mm.355690 Mm.2467 Mm.2651 Mm.30262

7.342 5.273 3.297 3.146 2.943 2.793 2.619 2.562 2.540 2.523 2.507 2.491 2.484 2.458 2.394 2.339 2.321 2.291 2.250 2.247 2.223 2.213 2.191 2.170 2.164 2.143 2.125 2.115 2.095 2.080 2.070 2.066 2.042 2.042 2.034 2.022 2.009 1.987 1.960 1.958 1.945 1.940 1.938 1.932 1.932 1.928 1.897 1.893 1.890 1.887

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TABLE S2 Continued. Common gene name Ankrd17 G6pdx Fech Arhgap21 Itm2b Grn Nr5a2 2410016F01Rik Ccm2 Glg1 Rec8L1 Tpd52 Flot2 Phf17 Mrps17 Pxn Myo1c Scrib Mt1 Flot2 Ilf3 Hcfc1 Rhog 9230112O05Rik Mat2a Cherp BC011248 Dnpep Cdca4 AI194308 Ormdl2 Ilk Gdi1 Slc6a8 Rps10 Chpt1 Gm542 Mea1 Suox BC011248 Pgrmc2 4930438M06Rik Uqcr Nxt1 Ssfa1 2400008B06Rik 5830484A20Rik 2810043O03Rik 0610025L06Rik Pros1

Genbank

UniGene

KAA/control

BM123013 NM_008062 NM_007998 BM213829 NM_008410 M86736 NM_030676 AB030190 BI903794 BG074127 BB390936 NM_009412 BB118974 BM197879 AK003008 BB530368 BQ176602 BC006859 NM_013602 NM_008028 NM_010561 BG864583 BG063931 BQ176370 AV260654 BC020488 NM_027910 BB407163 AF322238 NM_138752 BC002146 NM_010562 BC013758 BG069516 NM_025963 BC016251 BG066456 NM_025966 BC027197 BB229004 BQ175991 BE311335 NM_025650 NM_019761 BC026755 BC021788 BG072319 BF662697 AV010467 Z25469

Mm.245522 Mm.27210 Mm.1070 Mm.28507 Mm.4266 Mm.1568 Mm.16794 Mm.249986 Mm.221271 Mm.276271 Mm.23149 Mm.2777 Mm.3840 Mm.286285 Mm.249809 Mm.18714 Mm.234502 Mm.25568 Mm.192991 Mm.130227 Mm.20935 Mm.248353 Mm.302013 Mm.14155 Mm.29815 Mm.30136 Mm.45101 Mm.24680 Mm.313185 Mm.235700 Mm.319295 Mm.274846 Mm.205830 Mm.274553 Mm.275810 Mm.288897 Mm.8924 Mm.227011 Mm.23352 Mm.45101 Mm.40321 Mm.21912 Mm.43162 Mm.34663 Mm.299312 Mm.29148 Mm.335752 Mm.325955 Mm.21687 Mm.127156

1.874 1.869 1.867 1.852 1.841 1.803 1.801 1.801 1.783 1.757 1.747 1.747 1.740 1.737 1.719 1.706 1.705 1.703 1.703 1.695 1.693 1.692 1.672 1.668 1.644 1.628 1.628 1.601 1.588 1.585 1.550 1.548 1.511 1.509 1.492 1.484 1.454 1.452 1.449 1.444 1.417 1.411 1.406 1.404 1.395 1.395 1.394 1.380 1.380 1.347

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TABLE S2 Continued. Common gene name Nid1 4932432N11Rik Snx12 Carm1 Pcyt1a Bmpr1a Marcks 2310044H10Rik Bach1 Lrrc8 1110014J01Rik Cipp Bzw2 Kpnb1 Dctn6 Trp53inp1 D6Ertd245e Lmbr1 Chrac1 Hnrpa2b1 2410129E14Rik Ptprk Arfgap1 Phlda1 Smarce1 2310044D20Rik Ythdf1 LOC230761 Got2 Acly 1110008P14Rik Dsc2 Tnpo1 C76566 6530403A03Rik Rtn3 2310047C17Rik 8030450I18Rik D14Ertd209e; 2310032K15Rik Pnrc2 Lycat Rnpc2 1700037H04Rik Poldip3 Cog1 Calr Sms Shrm Hnrpa2b1

Genbank

UniGene

KAA/control

NM_010917 AK016542 BB414983 NM_021531 NM_009981 BM248248 BB454540 BC020179 NM_007520 BM942047 C80355 AV287690 BM932775 D67015 NM_011722 NM_021897 BG229246 BC016110 NM_053068 AU019883 AA986082 AI893646 BM196296 NM_009344 AK018493 BC021428 AV079675 BI409907 NM_010325 BI456232 C79326 BC004663 BI696984 BG065702 BC021443 NM_053076 BE570050 BB238427 AK009576

Mm.4691 Mm.85289 Mm.206949 Mm.230844 Mm.209300 Mm.237825 Mm.30059 Mm.294759 Mm.5183 Mm.297949 Mm.305939 Mm.291360 Mm.288669 Mm.251013 Mm.150373 Mm.28708 Mm.221038 Mm.41572 Mm.23095 Mm.155896 Mm.194735 Mm.332303 Mm.33765 Mm.3117 Mm.27330 Mm.272705 Mm.30205 Mm.22616 Mm.230169 Mm.282039 Mm.27608 Mm.280547 Mm.173286 Mm.345718 Mm.250783 Mm.246990 Mm.203866 Mm.135069 Mm.5750

1.344 1.341 1.322 1.299 1.292 1.281 1.277 1.257 1.250 1.244 1.225 1.216 1.215 1.210 1.208 1.204 1.203 1.198 1.192 1.190 1.183 1.178 1.172 1.168 1.166 1.165 1.163 1.161 1.155 1.149 1.136 1.122 1.117 1.115 1.113 1.113 1.112 1.109 1.103

NM_026383 BM237177 BG862129 NM_026091 BI963573 NM_013581 AW324084 NM_009214 NM_015756 C88150

Mm.29159 Mm.329194 Mm.153895 Mm.27711 Mm.23758 Mm.182445 Mm.1971 Mm.18652 Mm.46014 Mm.155896

1.097 1.097 1.092 1.090 1.087 1.083 1.082 1.079 1.076 1.073

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Vol. 86, Suppl 3, October 2006

TABLE S2 Continued. Common gene name Pgk1 4932431F02Rik Slc7a7 Hip1 Tacc2 Rb1cc1 Ggcx Ppp1r15b Rpn1 Eya3 Nup88 1200010C09Rik Hells; LSH; Lysh; PASG; YFK8 Becn1 Vil2 Fstl1 Cox6c Pycs Lrpap1 Gnpda1 Hist1h2bc Gata6 Rabac1 Cebpa Pomt2 H2afy Rap2b Nrarp A930017E24Rik Ube1x Sap18 Enpp1 Atp5f1 Slc6a14 Txndc4 Creb1 2010005O13Rik 1110032E23Rik Tm4sf3 Rps12 Cnot7; Caf1; Pop2 Mrps30 Hnrpa2b1 Luc7I2 Akr1b3 Glce Rab10 ElovI1 Cnbp

Genbank

UniGene

KAA/control

BB411302 BI408204 NM_011405 BB794880 BC004057 AB050017 BB488978 BC006897 BB145729 AI746570 BE951220 AK004688 NM_008234

Mm.316355 Mm.25610 Mm.142455 Mm.280805 Mm.302035 Mm.293811 Mm.19937 Mm.293628 Mm.188544 Mm.227733 Mm.288962 Mm.149870 Mm.57223

1.072 1.069 1.058 1.057 1.057 1.056 1.052 1.048 1.046 1.046 1.042 1.040 1.037

C86082 BM119387 BM225255 AV111078 BB251523 D00622 NM_011937 NM_023422 AF179425 L40934 BC011118 AF246235 AF171080 NM_028712 NM_025980 BC009152 NM_009457 BC006625 C76301 AK019459 AF320226 BM120687 AV016085 BC017549 NM_133187 C76990 NM_011295 AK007767 AV095945 NM_016806 BI076494 NM_009658 AK003758 BF465974 BB748075 AV299745

Mm.178947 Mm.277812 Mm.182434 Mm.548 Mm.233117 Mm.277661 Mm.22374 Mm.261676 Mm.329287 Mm.22473 Mm.35567 Mm.232537 Mm.283802 Mm.273288 Mm.46539 Mm.258142 Mm.1104 Mm.344671 Mm.27254 Mm.148721 Mm.253984 Mm.253136 Mm.1376 Mm.33535 Mm.331088 Mm.22270 Mm.300275 Mm.206770 Mm.353262 Mm.155896 Mm.276133 Mm.451 Mm.24411 Mm.74596 Mm.282096 Mm.7335

1.034 1.031 1.030 1.020 1.018 1.017 1.013 1.008 1.008 1.005 1.004 1.003 1.003 0.997 0.996 0.989 0.989 0.984 0.984 0.983 0.980 0.979 0.978 0.971 0.962 0.958 0.953 0.952 0.947 0.946 0.944 0.938 0.938 0.935 0.930 0.930

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TABLE S2 Continued. Common gene name G630055P03Rik Rac1 BC023957 Rps27I Hdgf Tpi Hgs Il11ra1 Lig3 Hibadh Mapk1 Rcn Cpne3 1110003H18Rik BC031407 2310014H01Rik Manba 9830165K03Rik Nnt Ebpl Tpi Tdgf1 Ddx5 Rpl31 Cbx1 Chd4 Stk3 Wasf2 Llglh C920006C10Rik; mKIAA0143 Akr1a4 1200013F24Rik Tfip11 Ephx2 H1f0 Gsta2 D8Ertd594e 2900024C23Rik Jund1 Pigo Ndrg1 Timm22 Rbpsuh Nkiras2 Crip1 Blnk Fts Capn7 BC019367

Genbank

UniGene

KAA/control

BG172318 AK011072 BI412808 BB836796 NM_008231 AW537828 BC003239 NM_016658 BM248530 BB805796 NM_011949 NM_009037 BB398005 AV053864 BC019178 NM_134122 NM_027288 BG069840 BB205930 BC027422 NM_009415 AV294613 AV114523 NM_053257 BB224832 BC005710 AY058922 BM207372 NM_008502 NM_133766

Mm.334775 Mm.292510 Mm.156565 Mm.30120 Mm.292208 Mm.4222 Mm.7919 Mm.193451 Mm.277136 Mm.286458 Mm.196581 Mm.4876 Mm.38390 Mm.33907 Mm.270044 Mm.279713 Mm.280536 Mm.28774 Mm.3842 Mm.22758 Mm.4222 Mm.5090 Mm.220038 Mm.298467 Mm.29055 Mm.183257 Mm.262330 Mm.23566 Mm.285453 Mm.260647

0.927 0.927 0.921 0.918 0.913 0.911 0.903 0.901 0.900 0.897 0.895 0.887 0.886 0.879 0.878 0.875 0.875 0.874 0.869 0.867 0.863 0.859 0.853 0.850 0.846 0.846 0.845 0.844 0.842 0.840

AK009462 NM_025822 NM_018783 NM_007940 NM_008197 NM_008182 NM_133791 BM114165 NM_010592 BB546713 NM_008681 AK012130 NM_009035 BC024398 NM_007763 AF068182 AW490901 BQ179335 BC019367

Mm.30085 Mm.33969 Mm.172947 Mm.15295 Mm.24350 Mm.197422 Mm.235074 Mm.277897 Mm.1175 Mm.143738 Mm.30837 Mm.18803 Mm.209292 Mm.274734 Mm.272368 Mm.9749 Mm.279449 Mm.201535 Mm.125288

0.834 0.830 0.824 0.823 0.822 0.816 0.810 0.809 0.808 0.806 0.805 0.804 0.793 0.779 0.774 0.770 0.758 0.753 0.747

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1265.e29 Rinaudo et al.

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Vol. 86, Suppl 3, October 2006

TABLE S2 Continued. Common gene name Rpo1-4 Il6 Tfpi Hspa4 Kcmf1 BC017133 Tpm1 Fzd7 9030418M05Rik Niban Gm2a Ppp1cb Orc4l Idb2 Snap29 1110007A06Rik Dppa3 Trap1a Atp2a2 Ube2a 1700012G19Rik BC016423 1200013l08Rik 2410018G23Rik Sox2 Soat1 Lamb1-1 2310057G13Rik Nap1I1 1700009P03Rik Ndufs4 1200003C05Rik Lman2 Dnajc3 Pdcd6ip Chchd3 5430433L24Rik Cct2 Eif4a1 Msh6 Eif4g2 Golph3 2210401K01Rik 2010012F05Rik Suclg1 2600005C20Rik 2310056P07Rik AcsI6 Vdac1 Fbln1

Genbank

UniGene

KAA/control

BB044828 NM_031168 AF004833 AW909503 NM_019715 BC017133 M22479 AK010239 NM_133681 NM_022018 NM_010299 M27073 BM114162 NM_010496 BF682880 BG795169 AY082485 NM_011635 NM_009722 BG868960 AK012010 NM_134063 BI738010 BB815513 U31967 NM_009230 M15525 AK009957 BG064031 AW544305 NM_010887 BC002238 AK004952 AV024539 BM246857 BC021941 AV293164 AV172084 BF320852 BM250164 NM_013507 AV174110 AA560093 BC011429 NM_019879 AV228374 BC010826 BC022959 AV036172 BC007140

Mm.135581 Mm.1019 Mm.124316 Mm.239865 Mm.29194 Mm.287208 Mm.121878 Mm.297906 Mm.45994 Mm.157700 Mm.287807 Mm.241931 Mm.21834 Mm.34871 Mm.271992 Mm.28474 Mm.27982 Mm.1297 Mm.227583 Mm.172835 Mm.28541 Mm.221609 Mm.26696 Mm.28626 Mm.4541 Mm.28099 Mm.172674 Mm.245537 Mm.337558 Mm.291542 Mm.253142 Mm.278477 Mm.38868 Mm.12616 Mm.29816 Mm.21501 Mm.23846 Mm.247788 Mm.328549 Mm.18210 Mm.185453 Mm.250936 Mm.298256 Mm.262480 Mm.29845 Mm.255881 Mm.212991 Mm.267478 Mm.3555 Mm.297992

0.731 0.721 0.718 0.711 0.697 0.683 0.664 0.657 0.640 0.631 0.627 0.626 0.613 0.592 0.587 0.586 0.584 0.584 0.579 0.577 0.566 0.566 0.562 0.562 0.550 0.548 0.543 0.535 0.534 0.522 0.519 0.518 0.510 0.510 0.508 0.500 0.495 0.491 0.490 0.489 0.488 0.486 0.486 0.484 0.484 0.482 0.472 0.471 0.466 0.465

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TABLE S2 Continued. Common gene name Rpl22 Hibadh Asns Uqcrc2 Ppp1cb Trip11 Nutf2 Arid5b Cldn3 Tmsb10 1810073P09Rik 5033405D03Rik BC019806 Tcfcp2I2 Ndrg1 1110064P04Rik Il6st Lgals4 Pla2g10 Pdzk1; Pdzd1; mPDZK1; D3Ertd537e 2610101N10Rik 3110003A17Rik Tiparp Chka Adam19 Tm4sf3 Lcp1 B3gnt5 Pygb Plekhc1 Slc15a2 Saa3 Mtm1 1300002F13Rik NoI5a Aqp8 Cklfsf7 Mgea5 Slc40a1 Pitrm1 Rdx Arpc1b Dnmt3a 3110043J09Rik Slc7a3 Tgfbi Slc6a14 Ube2a

Genbank

UniGene

KAA/control

BC021344 BC003914 BC005552 AV082188 AW823525 AV013785 BC003955 BB699910 BC012650 BB096368 AK007980 BB559878 AV094699 BC013080 AI790290 BM120737 AK017211 BC021632 AF166097 AK006269

Mm.307846 Mm.286458 Mm.2942 Mm.988 Mm.241931 Mm.355302 Mm.306812 Mm.270346 Mm.158662 Mm.346305 Mm.202157 Mm.19352 Mm.202257 Mm.263068 Mm.30837 Mm.13148 Mm.4364 Mm.210336 Mm.4214 Mm.28015

0.460 0.459 0.447 0.438 0.437 0.435 0.434 0.429 0.428 0.427 0.423 0.422 0.419 0.414 0.412 0.411 0.409 0.408 0.408 0.405

BM247469 AK013984 BB762264 NM_013490 D50410 BC025461 BC022943 BM214359 AW547988 BE994235 NM_021301 NM_011315 NM_019926 NM_133753 BF660256 NM_007474 NM_133978 NM_023799 BC003438 AW763881 NM_009041 BC010275 BB702511 BC010306 NM_007515 BB532080 NM_020049 NM_019668

Mm.292742 Mm.276041 Mm.246398 Mm.225505 Mm.89940 Mm.22270 Mm.153911 Mm.33935 Mm.222584 Mm.210018 Mm.281804 Mm.14277 Mm.274981 Mm.249333 Mm.29363 Mm.273175 Mm.35600 Mm.122725 Mm.28756 Mm.41933 Mm.245746 Mm.30010 Mm.5001 Mm.128411 Mm.5140 Mm.14455 Mm.253984 Mm.172835

0.403 0.395 0.395 0.390 0.387 0.386 0.375 0.365 0.363 0.356 0.355 0.346 0.344 0.336 0.322 0.321 0.316 0.316 0.305 0.300 0.299 0.292 0.291 0.284 0.282 0.282 0.277 0.269

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TABLE S2 Continued. Common gene name Hnrph2 Camk1 Uhrf1 Mitf Slc15a2 Spp1 Morc Upp1 Ndr1

Genbank

UniGene

KAA/control

NM_019868 NM_133926 NM_010931 BB763517 BC018335 NM_009263 NM_010816 NM_009477 AV309418

Mm.315909 Mm.277373 Mm.42196 Mm.100641 Mm.281804 Mm.288474 Mm.250060 Mm.4610 Mm.4063

0.267 0.261 0.261 0.249 0.238 0.209 0.174 0.164 0.145

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TABLE S3 Numbers of oxygen-regulated genes.

ARE genes Hyperoxic genes Total hyperoxic HRE genes Hypoxic genes Total hypoxic

No. genes in the literature

No. genes in the Affymetrix chip

No. genes expressed

60 14 74 51 14 65

51 13 64 41 14 55

22 6 28 15 2 17

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TABLE S4 Hypoxic genes.

Hypoxic genes Adm Adra1b ALDOA Arnt2 Arnt1 Bnip3 Cited2 Cp Ctgf Cxcr4 Cyp4b1 Edn1 Eng Eno1 Epor Ets1 Fech Flt1 Furin Gck Hif1a Hk1 Hk2 Igf2 Igfbp1 Igfbp2 Igfbp3 Ldh1 Lep Mcl1 Met Mt1 Nos2 Npm1 Npm3 Pak3 P4hb Pck2 Pfkfb3 Pfk1 Pgk1 Pkm2 Pmaip1 Ppp5c Rora Serpine1 Slc2a1

Gene bank ID

Unigene ID

Genes present on the chip

NM_009627 NM_007416 NM_007438 AI428888 BC011080 NM_009760 NM_010828 BB332449 NM_010217 D87747 NM_007823 D43775 NM_007932 NM_023119 AK010968 BC010588 NM_007998 NM_010228 NM_011046 BC011139 X95580 NM_010438 NM_013820 NM_010514 NM_008341 AK011784 AV175389 NM_010699 U18812 BC003839 NM_008591 NM_013602 AF065921 NM_008722 BB811478 BQ174935 BM232513 BC010318 NM_133232 NM_008826 BB411302 NM_011099 NM_021451 BC003744 NM_013646 NM_008871 BM207588

Mm.1408 Mm.39086 Mm.16763 Mm.4813 Mm.12177 Mm.2159 Mm.272321 Mm.13787 Mm.1810 Mm.1401 Mm.1840 Mm.14543 Mm.225297 Mm.70666 Mm.2653 Mm.292415 Mm.1070 Mm.3464 Mm.5241 Mm.220358 Mm.3879 Mm.196605 Mm.255848 Mm.3862 Mm.21300 Mm.141936 Mm.29254 Mm.29324 Mm.277072 Mm.1639 Mm.86844 Mm.192991 Mm.2893 Mm.6343 Mm.1406 Mm.3392 Mm.16660 Mm.29856 Mm.19669 Mm.269649 Mm.316355 Mm.335209 Mm.271878 Mm.3294 Mm.267116 Mm.1263 Mm.21002

⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹

Genes expressed in blastocyst ⫺ ⫺ ⫺ ⫺ ⫺ ⫹ ⫺ ⫺ ⫹ ⫺ ⫺ ⫺ ⫺ ⫹ ⫺ ⫺ ⫹ ⫺ ⫺ ⫺ ⫺ ⫺ ⫹ ⫺ ⫺ ⫺ ⫺ ⫹ ⫺ ⫹ ⫺ ⫹ ⫺ ⫹ ⫺ ⫺ ⫹ ⫺ ⫺ ⫹ ⫹ ⫹ ⫹ ⫹ ⫺ ⫺ ⫹

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TABLE S4 Continued.

Hypoxic genes Slc2a3 Tert Tfrc Tgfb3 Trf Vegfa Vegfb Vegfc Wt1 Epo Gapd Glut1(similar) Gnn Ndg1 Ndg2 Npm2 Pfkfb4

Gene bank ID

Unigene ID

Genes present on the chip

M75135 NM_009354 BB810450 BC014690 AF440692 NM_009505 U48800 NM_009506 M55512 NM_007942 BC083080 AK165453 AY651022 NM_183322 NM_175329 AY262112 BE136572

Mm.3726 Mm.10109 Mm.28683 Mm.307887 Mm.37214 Mm.282184 Mm.15607 Mm.1402 Mm.246679 Mm.349116 Mm.379644 Mm.332530 Mm.200446 Mm.26006 Mm.333849 Mm.347749 Mm.132391

⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫺ ⫺ ⫺ ⫺ ⫺ ⫺ ⫺ ⫺

Genes expressed in blastocyst ⫺ ⫺ ⫺ ⫺ ⫺ ⫺ ⫺ ⫺ ⫺ ⫺ ⫺ ⫺ ⫺ ⫺ ⫺ ⫺ ⫺

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TABLE S5 Hyperoxic genes. Hyperoxic genes 2410003B16Rik Abcb6 Agl Akr1c6 Axin1 Bambi Bax Bdkrb2 Bid3 Cacna1e Catnb Chml Cnr1 Col16a1 Crk1 Dnchc1 Emilin1 Enpp2 Ercc5 Fhl2 Fth1 Ftl1 Gadd45b Gclc Gclm Gpc1 Gsr Gstm3 Herpud1 Hmox1 Hnrph1 Hspa5 Hspa8 Ilf3 Keap1 Map1lc3a Map2k4 Msi1h Msi2h Mta1 Mxd4 Nefh Nf2 Nqo1 Nup153 Olfm1 Pcdh8 Pex5 Pik4ca

Gene bank ID

Unigene ID

Genes present on the chip

Genes expressed in blastocyst

AF205078 NM_023732 AA681807 NM_030611 BB004060 AF153440 BC018228 NM_009747 NM_007545 NM_009782 NM_007614 NM_021350 NM_007726 BB766878 BB402776 NM_030238 NM_133918 BC003264 BM198879 NM_010212 AK002778 NM_008049 AK010420 BC019374 NM_008129 NM_016696 AK019177 J03953 AI835088 NM_010442 NM_021510 NM_022310 BC006722 NM_010561 AW764104 BC010596 BM240207 BB414973 BI696168 NM_054081 BE291523 M35131 L28176 AV158882 BB292874 BE952082 NM_021543 NM_008995 BM207220

Mm.29933 Mm.28663 Mm.237099 Mm.196666 Mm.23684 Mm.284863 Mm.19904 Mm.4500 Mm.21912 Mm.329373 Mm.291928 Mm.103763 Mm.7992 Mm.41860 Mm.202379 Mm.181430 Mm.286375 Mm.28107 Mm.2213 Mm.6799 Mm.182962 Mm.30357 Mm.1360 Mm.89888 Mm.292676 Mm.24193 Mm.283573 Mm.347436 Mm.29151 Mm.276389 Mm.21740 Mm.330160 Mm.290774 Mm.20935 Mm.248266 Mm.196239 Mm.27491 Mm.5077 Mm.23878 Mm.212577 Mm.38795 Mm.298283 Mm.297109 Mm.252 Mm.255398 Mm.43278 Mm.103811 Mm.22418 Mm.5718

⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹

⫹ ⫹ ⫺ ⫺ ⫺ ⫹ ⫹ ⫺ ⫺ ⫺ ⫹ ⫺ ⫺ ⫺ ⫺ ⫹ ⫺ ⫺ ⫹ ⫹ ⫺ ⫹ ⫺ ⫹ ⫹ ⫺ ⫺ ⫺ ⫺ ⫹ ⫹ ⫹ ⫺ ⫺ ⫹ ⫹ ⫺ ⫺ ⫺ ⫺ ⫺ ⫺ ⫹ ⫺ ⫹ ⫺ ⫺ ⫺ ⫹

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TABLE S5 Continued. Hyperoxic genes Pld3 Pls3 Psmb4 Prkr Rabgap1 Rassf2 Scg2 Sfrs6 Sntb2 Sqstm1 Ssr4 Tkt Trim16 Txnrd1 Wnt5a Zfp3612 4932442E05Rik Dhdh Myh10 Sstk Zfp184 Zfp263 Zfp3612 Ireb2

Gene bank ID

Unigene ID

Genes present on the chip

Genes expressed in blastocyst

NM_011116 BC005459 AV212146 NM_025774 BB486322 AK018504 NM_009129 AW539046 BB219478 BM232298 AV051818 AI314476 BB834440 NM_015762 BB067079 BB031791 BE374941 AK005050 BB291766 NM_032004 BB129967 AI326880 BB031791 BM201500

Mm.6483 Mm.28777 Mm.368 Mm.31643 Mm.74753 Mm.204737 Mm.5038 Mm.24042 Mm.30228 Mm.40828 Mm.200990 Mm.290692 Mm.117087 Mm.210155 Mm.287544 Mm.28161 Mm.103617 Mm.34208 Mm.131761 Mm.69431 Mm.187444 Mm.202678 Mm.28161 Mm.218563

⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫺ ⫺ ⫺ ⫺ ⫺ ⫺ ⫺ ⫺

⫹ ⫹ ⫹ ⫺ ⫹ ⫺ ⫺ ⫹ ⫺ ⫹ ⫺ ⫹ ⫺ ⫹ ⫺ ⫺ ⫺ ⫺ ⫺ ⫺ ⫺ ⫺ ⫺ ⫺

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