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Assignment of the Hypoxia-Inducible Factor 1α Gene to a Region of Conserved Synteny on Mouse Chromosome 12 and Human Chromosome 14q
SHORT COMMUNICATION Assignment of the Hypoxia-Inducible Factor 1a Gene to a Region of Conserved Synteny on Mouse Chromosome 12 and Human Chromosome 14q G. L. SEMENZA,*,1 E. A. RUE,* N. V. IYER,* M. G. PANG,†
AND
W. G. KEARNS*,†
*Center for Medical Genetics, Departments of Pediatrics and Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287; and †Center for Pediatric Research, Department of Pediatrics, Eastern Virginia Medical School, Norfolk, Virginia 23510 Received December 26, 1995; accepted April 3, 1996
Hypoxia-inducible factor 1 (HIF-1) is a basic helix– loop – helix transcription factor that mediates homeostatic responses to hypoxia. HIF-1 is a heterodimer consisting of HIF-1a, which is encoded by the HIF1A gene, complexed with HIF-1b, which is encoded by the ARNT gene. In this paper we report the assignment of Hif1a and HIF1A to mouse chromosome 12 and human chromosome 14, respectively. HIF1A was assigned to human chromosome 14q21 – q24 by analysis of somatic cell hybrids and by fluorescence in situ hybridization. Hif1a was localized by interspecific backcross analysis within a region of mouse chromosome 12 encompassing ú30 cM that demonstrates conservation of synteny with a region of human chromosome 14 extending from PAX9 at 14q12– q13 to IGHC at 14q32.33. q 1996 Academic Press, Inc.
HIF-1 has been implicated in the transcriptional activation within hypoxic cells of genes encoding erythropoietin (EPO); the glycolytic enzymes aldolase A, enolase 1, lactate dehydrogenase A, phosphofructokinase L, and phosphoglycerate kinase 1; inducible nitric oxide synthase (i-NOS); and vascular endothelial growth factor (VEGF) (reviewed in Ref. 11). These gene products all participate in homeostatic responses to hypoxia that either increase oxygen delivery to hypoxic tissues (EPO, i-NOS, VEGF) or activate an alternative metabolic pathway (glycolysis) that does not require O2 (7). Purification of HIF-1 and isolation of cognate cDNA sequences revealed that HIF-1 was a heterodimeric protein composed of two basic helix–loop –helix subunits, HIF-1a and HIF-1b (10, 12). HIF-1a cDNA sequences encoded a unique polypeptide of 826 amino acids, whereas HIF-1b was identical to the aryl hydrocarbon receptor (AHR) nuclear translocator (ARNT) protein, which was previously isolated and characterized as a subunit of the mammalian AHR complex (3). 1 To whom correspondence should be addressed at Johns Hopkins Hospital, CMSC-1004, 600 N. Wolfe Street, Baltimore, MD 212873914. Telephone: (410) 955-1619. Fax: (410) 955-0484. E-mail: [email protected].
ARNT can thus heterodimerize with AHR in cells exposed to aryl hydrocarbons such as dioxin to form the AHR complex or it can heterodimerize with HIF-1a in cells subjected to hypoxia to form HIF-1. The ARNT gene encoding the HIF-1b subunit has been previously mapped to human chromosome 1q21 and mouse chromosome 3 (4). The purpose of this study was to map the human (HIF1A) and mouse (Hif1a) genes that encode the HIF-1a subunit. To perform linkage analysis, we isolated a 0.29-kb fragment of the mouse Hif1a gene by PCR amplification of mouse genomic DNA using oligonucleotide primers derived from the human HIF-1a 3*-untranslated region (12). Nucleotide sequence analysis revealed that the cloned mouse DNA (excluding primers) was 83% identical to the corresponding human HIF-1a sequence and hybridized to HIF-1a mRNA on Northern blots (data not shown), confirming its identity as the homologous mouse sequence. Blot hybridization analysis of C57BL/6J and Mus spretus genomic DNA using the 0.29-kb probe revealed that Hif1a is a single-copy mouse gene and identified an interspecific EcoRI restriction fragment length polymorphism. DNA samples from the offspring of a (C57BL/6J 1 M. spretus)F1 1 M. spretus (BSS) backcross mating (6) were genotyped for the Hif1a polymorphism. Data were submitted to the Jackson Laboratory for linkage analysis. Comparison of these data with results obtained for over 2000 loci previously mapped on the BSS panel (L. Rowe, pers. comm., Oct. 1995) indicated that Hif1a is located on mouse chromosome 12, approximately 1.1 cM distal to D12Bir3 and 1.1 cM proximal to D12Mit3 (Fig. 1A). The reciprocal (C57BL/6J 1 M. spretus)F1 1 C57BL/6J (BSB) backcross panel, on which approximately 700 loci have been mapped, including D12Mit3 but not D12Bir3, was also screened. Hif1a mapped to a position 4.9 cM proximal to D12Mit3 (data not shown). Combining the data from the BSS and BSB panels, the fraction of mice showing recombination between Hif1a and D12Mit3 was 1/90 (BSS; Fig. 1B) / 4/89 (BSB; data not shown) or 5/179. Based upon these data, the genetic distance between these loci is estimated to be 2.8 cM, GENOMICS
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34, 437–439 (1996) ARTICLE NO. 0311
0888-7543/96 $18.00 Copyright q 1996 by Academic Press, Inc. All rights of reproduction in any form reserved.
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05-16-96 00:13:19
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FIG. 1. Assignment of Hif1a to mouse chromosome 12. (A) Partial linkage map of chromosome 12. Genetic distance (in centimorgans) between loci is indicated, based upon data from the BSS backcross panel. Anonymous DNA markers and known genes are indicated to the left and right, respectively. (B) Segregation patterns of Hif1a and flanking markers on chromosome 12 in offspring of the BSS backcross mating. Inheritance of C57BL/6J (solid boxes) or M. spretus (open boxes) alleles and number of offspring that inherited each haplotype are indicated.
with 95% confidence limits of 0.9 to 6.5 cM. The fraction of BSS mice showing recombination between Hif1a and D12Bir3 was 1/91 (Fig. 1B), giving an estimated genetic distance of 1.1 cM, with 95% confidence limits of 0.0 to 6.0 cM. To map the human HIF1A gene, EcoRI-digested DNA samples from 18 rodent 1 human somatic cell hybrids segregating multiple human chromosomes (BIOS Laboratories, New Haven CT) were analyzed by blot hybridization for the presence of the human HIF1A gene using a 3.6-kb human HIF-1a cDNA probe (12). All 4 hybrids containing human chromosome 14 were positive for human HIF-1a sequences, and all 14 hybrids lacking chromosome 14 were negative for human HIF-1 a sequences (data not shown). Discordant segregation (§17%) was observed for all other human chromosomes. To confirm these results, DNA from a panel of 24 rodent 1 human somatic cell hybrids, each containing a unique human chromosome (BIOS Laboratories), was analyzed by PCR using a set of primers that amplify a 129-bp HIF-1a DNA sequence from human, but not from mouse or hamster, genomic DNA. The expected amplification
AID Genom 4115
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product was detected only when DNA from the hybrid containing human chromosome 14 was assayed (Fig. 2A). In addition, the results of blot hybridization analysis of hybrids segregating multiple human chromosomes were confirmed by PCR (data not shown). Thus, using two different somatic cell hybrid panels and two different assay methods, we have assigned the HIF1A locus to human chromosome 14. To determine the cytogenetic location of the HIF1A locus, FISH analysis of metaphase chromosomes (2) was performed using as probe a biotin-labeled 11-kb EcoRI fragment from the human HIF1A gene. The hybridization signal was restricted to a single D-group acrocentric chromosome (Fig. 2B). Digoxigenin-labeled probes specific for a-satellite DNA from chromosome 13 (D13Z1) or chromosome 15 (D15Z1) did not colocalize with the HIF1A signal (data not shown). In contrast, a digoxigenin-labeled YAC containing human genomic DNA previously mapped to chromosome 14q32 (D14S632) colocalized with the HIF1A signal on 24 of 31 metaphase spreads examined (Fig. 2B). These data confirm the results obtained by analysis of somatic cell hybrids and provide subchromosomal localization of HIF1A to the region encompassed by bands 14q21–q24 based upon the position of the HIF1A and D14S632 signals relative to the centromere. The human and mouse genes encoding the HIF-1a subunit of the transcription factor HIF-1 have been designated HIF1A (GDB Accession No. G00-512-229) and Hif1a (Accession Nos. MGD-CREX-495 and MGDCREX-496) by the Human and Mouse Genome Databases, respectively. In this study, we mapped the Hif1a locus to mouse chromosome 12, approximately 1.1 cM distal to the marker D12Bir3 and 1.1 cM proximal to the marker D12Mit3. These results localize Hif1a within a region of mouse chromosome 12, spanning a genetic distance of greater than 30 cM, that demonstrates conservation of synteny with a region of human chromosome 14 from 14q12 –q13 (PAX9) to 14q32.33 (IGHC) (1, 8). As predicted by these data, the HIF1A locus was assigned to human chromosome 14 based upon analysis of two different human 1 rodent somatic cell hybrid panels. Independent analysis by fluorescence in situ hybridization (FISH) confirmed the assignment and provided cytogenetic subchromosomal localization to the 14q21 –q24 region. Thus the genes HIF1A and ARNT, encoding the two subunits of HIF1, have been assigned to two different human chromosomes, 14q21–q24 and 1q21, respectively. Review of the Mouse Genome Database failed to reveal any mouse mutations that have been mapped in close proximity to Hif1a. In humans, the translocation t(12;14)(q13 –q15;q23– q24) has been identified in uterine leiomyomata (9). The 16 expressed sequence tags in the dbest database (as of December 1995) that have identity to the HIF-1a cDNA sequence (12) include a clone isolated from a uterus cDNA library (GenBank Accession No. T32012). Given the considerable number of neoplasia-specific translocations that involve genes encoding transcription factors (5), it may be of interest
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SHORT COMMUNICATION
FIG. 2. Assignment of HIF1A to human chromosome 14. (A) PCR analysis of rodent 1 human monochromosomal hybrids for the presence of HIF1A sequences. DNA samples from somatic cell hybrids, each containing a unique human chromosome (1–22, X, Y), were assayed by PCR using HIF1A oligonucleotide primers that amplify a 129-bp DNA fragment from human genomic DNA (H). fx, HaeIII digestion of fx174 DNA. Arrow, 129-bp PCR product (lanes H and 14). (B) Localization of HIF1A to human chromosome 14q21 –q24. Two-probe, twocolor FISH analysis of human metaphase chromosomes was performed using a biotin-labeled HIF1A probe (green) and a digoxigenin-labeled YAC probe (D14S632) previously mapped to 14q32 (red). Chromosomes were counterstained with DAPI (purple).
to establish the position of the HIF1A locus relative to the leiomyoma-associated translocation breakpoint on chromosome 14. 5.
ACKNOWLEDGMENTS 6. We are grateful to Lucy Rowe and the Jackson Laboratory DNA Resource for assistance with interspecific backcross analysis; Sue Povey and Lois Maltais for human and mouse locus nomenclature assignment; and Roger Reeves for review of the manuscript. G.L.S. is an Established Investigator of the American Heart Association, and this work was supported by grants from the American Heart Association, the Lucille P. Markey Charitable Trust, and the National Institutes of Health (DK-39869).
7.
8.
REFERENCES 1. D’Eustachio, P. D. (1994). Mouse chromosome 12. Mamm. Genome 5(Suppl): S181–S195. 2. Geraghty, M. T., Kearns, W. G., Pearson, P. L., and Valle, D. (1993). Isolation and characterization of an ornithine aminotransferase-related sequence (OATL3) mapping to 10q26. Genomics 17: 510–513. 3. Hoffman, E. C., Reyes, H., Chu, F.-F., Sander, F., Conley, L. H., Brooks, B. A., and Hankinson, O. (1991). Cloning of a factor required for activity of the Ah (dioxin) receptor. Science 252: 954–958. 4. Johnson, B., Brooks, B. A., Heinzmann, C., Diep, A., Mohandas, T., Sparkes, R. S., Reyes, H., Hoffman, E., Lange, E., Gatti,
AID Genom 4115
/
6r16$$$521
05-16-96 00:13:19
9.
10.
11. 12.
R. A., Xia, Y.-R., Lusis, A. J., and Hankinson, O. (1993). The Ah receptor nuclear translocator gene (ARNT) is located on q21 of human chromosome 1 and on mouse chromosome 3 near Cf3. Genomics 17: 592–598. Rabbitts, T. H. (1994). Chromosomal translocations in human cancer. Nature 372: 143–149. Rowe, L. B., Nadeau, J. H., Turner, R., Frankel, W. R., Letts, V. A., Eppig, J. T., Ko, M. S. H., Thurston, S. J., and Birkenmeier, E. H. (1994). Maps from two interspecific backcross DNA panels available as a community genetic mapping resource. Mamm. Genome 5: 253–274. Semenza, G. L. (1994). Regulation of erythropoietin production: New insights into molecular mechanisms of oxygen homeostasis. Hematol. Oncol. Clin. N. Am. 8: 863 –884. Stapleton, P., Weith, A., Urbanek, P., Koznik, Z., and Busslinger, M. (1993). Chromosomal localization of seven PAX genes and cloning of a novel family member, PAX-9. Nat. Genet. 3: 292– 298. Trent, J. M., Kaneko, Y., and Mitelman, F. (1989). Report of the committee on structural chromosome changes in neoplasia. Cytogenet. Cell Genet. 51: 533– 562. Wang, G. L., and Semenza, G. L. (1995). Purification and characterization of hypoxia-inducible factor 1. J. Biol. Chem. 270: 1230 –1237. Wang, G. L., and Semenza, G. L. (1996). Oxygen sensing and response to hypoxia by mammalian cells. Redox Rep. 2: 89–96. Wang, G. L., Jiang, B.-H., Rue, E. A., and Semenza, G. L. (1995). Hypoxia-inducible factor 1 is a basic – helix– loop –helix –PAS heterodimer regulated by cellular O 2 tension. Proc. Natl. Acad. Sci. USA 92: 5510 –5514.
gnmxal
AP: Genomics
AND
W. G. KEARNS*,†
*Center for Medical Genetics, Departments of Pediatrics and Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287; and †Center for Pediatric Research, Department of Pediatrics, Eastern Virginia Medical School, Norfolk, Virginia 23510 Received December 26, 1995; accepted April 3, 1996
Hypoxia-inducible factor 1 (HIF-1) is a basic helix– loop – helix transcription factor that mediates homeostatic responses to hypoxia. HIF-1 is a heterodimer consisting of HIF-1a, which is encoded by the HIF1A gene, complexed with HIF-1b, which is encoded by the ARNT gene. In this paper we report the assignment of Hif1a and HIF1A to mouse chromosome 12 and human chromosome 14, respectively. HIF1A was assigned to human chromosome 14q21 – q24 by analysis of somatic cell hybrids and by fluorescence in situ hybridization. Hif1a was localized by interspecific backcross analysis within a region of mouse chromosome 12 encompassing ú30 cM that demonstrates conservation of synteny with a region of human chromosome 14 extending from PAX9 at 14q12– q13 to IGHC at 14q32.33. q 1996 Academic Press, Inc.
HIF-1 has been implicated in the transcriptional activation within hypoxic cells of genes encoding erythropoietin (EPO); the glycolytic enzymes aldolase A, enolase 1, lactate dehydrogenase A, phosphofructokinase L, and phosphoglycerate kinase 1; inducible nitric oxide synthase (i-NOS); and vascular endothelial growth factor (VEGF) (reviewed in Ref. 11). These gene products all participate in homeostatic responses to hypoxia that either increase oxygen delivery to hypoxic tissues (EPO, i-NOS, VEGF) or activate an alternative metabolic pathway (glycolysis) that does not require O2 (7). Purification of HIF-1 and isolation of cognate cDNA sequences revealed that HIF-1 was a heterodimeric protein composed of two basic helix–loop –helix subunits, HIF-1a and HIF-1b (10, 12). HIF-1a cDNA sequences encoded a unique polypeptide of 826 amino acids, whereas HIF-1b was identical to the aryl hydrocarbon receptor (AHR) nuclear translocator (ARNT) protein, which was previously isolated and characterized as a subunit of the mammalian AHR complex (3). 1 To whom correspondence should be addressed at Johns Hopkins Hospital, CMSC-1004, 600 N. Wolfe Street, Baltimore, MD 212873914. Telephone: (410) 955-1619. Fax: (410) 955-0484. E-mail: [email protected].
ARNT can thus heterodimerize with AHR in cells exposed to aryl hydrocarbons such as dioxin to form the AHR complex or it can heterodimerize with HIF-1a in cells subjected to hypoxia to form HIF-1. The ARNT gene encoding the HIF-1b subunit has been previously mapped to human chromosome 1q21 and mouse chromosome 3 (4). The purpose of this study was to map the human (HIF1A) and mouse (Hif1a) genes that encode the HIF-1a subunit. To perform linkage analysis, we isolated a 0.29-kb fragment of the mouse Hif1a gene by PCR amplification of mouse genomic DNA using oligonucleotide primers derived from the human HIF-1a 3*-untranslated region (12). Nucleotide sequence analysis revealed that the cloned mouse DNA (excluding primers) was 83% identical to the corresponding human HIF-1a sequence and hybridized to HIF-1a mRNA on Northern blots (data not shown), confirming its identity as the homologous mouse sequence. Blot hybridization analysis of C57BL/6J and Mus spretus genomic DNA using the 0.29-kb probe revealed that Hif1a is a single-copy mouse gene and identified an interspecific EcoRI restriction fragment length polymorphism. DNA samples from the offspring of a (C57BL/6J 1 M. spretus)F1 1 M. spretus (BSS) backcross mating (6) were genotyped for the Hif1a polymorphism. Data were submitted to the Jackson Laboratory for linkage analysis. Comparison of these data with results obtained for over 2000 loci previously mapped on the BSS panel (L. Rowe, pers. comm., Oct. 1995) indicated that Hif1a is located on mouse chromosome 12, approximately 1.1 cM distal to D12Bir3 and 1.1 cM proximal to D12Mit3 (Fig. 1A). The reciprocal (C57BL/6J 1 M. spretus)F1 1 C57BL/6J (BSB) backcross panel, on which approximately 700 loci have been mapped, including D12Mit3 but not D12Bir3, was also screened. Hif1a mapped to a position 4.9 cM proximal to D12Mit3 (data not shown). Combining the data from the BSS and BSB panels, the fraction of mice showing recombination between Hif1a and D12Mit3 was 1/90 (BSS; Fig. 1B) / 4/89 (BSB; data not shown) or 5/179. Based upon these data, the genetic distance between these loci is estimated to be 2.8 cM, GENOMICS
437
34, 437–439 (1996) ARTICLE NO. 0311
0888-7543/96 $18.00 Copyright q 1996 by Academic Press, Inc. All rights of reproduction in any form reserved.
AID Genom 4115
/
6r16$$$521
05-16-96 00:13:19
gnmxal
AP: Genomics
438
SHORT COMMUNICATION
FIG. 1. Assignment of Hif1a to mouse chromosome 12. (A) Partial linkage map of chromosome 12. Genetic distance (in centimorgans) between loci is indicated, based upon data from the BSS backcross panel. Anonymous DNA markers and known genes are indicated to the left and right, respectively. (B) Segregation patterns of Hif1a and flanking markers on chromosome 12 in offspring of the BSS backcross mating. Inheritance of C57BL/6J (solid boxes) or M. spretus (open boxes) alleles and number of offspring that inherited each haplotype are indicated.
with 95% confidence limits of 0.9 to 6.5 cM. The fraction of BSS mice showing recombination between Hif1a and D12Bir3 was 1/91 (Fig. 1B), giving an estimated genetic distance of 1.1 cM, with 95% confidence limits of 0.0 to 6.0 cM. To map the human HIF1A gene, EcoRI-digested DNA samples from 18 rodent 1 human somatic cell hybrids segregating multiple human chromosomes (BIOS Laboratories, New Haven CT) were analyzed by blot hybridization for the presence of the human HIF1A gene using a 3.6-kb human HIF-1a cDNA probe (12). All 4 hybrids containing human chromosome 14 were positive for human HIF-1a sequences, and all 14 hybrids lacking chromosome 14 were negative for human HIF-1 a sequences (data not shown). Discordant segregation (§17%) was observed for all other human chromosomes. To confirm these results, DNA from a panel of 24 rodent 1 human somatic cell hybrids, each containing a unique human chromosome (BIOS Laboratories), was analyzed by PCR using a set of primers that amplify a 129-bp HIF-1a DNA sequence from human, but not from mouse or hamster, genomic DNA. The expected amplification
AID Genom 4115
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product was detected only when DNA from the hybrid containing human chromosome 14 was assayed (Fig. 2A). In addition, the results of blot hybridization analysis of hybrids segregating multiple human chromosomes were confirmed by PCR (data not shown). Thus, using two different somatic cell hybrid panels and two different assay methods, we have assigned the HIF1A locus to human chromosome 14. To determine the cytogenetic location of the HIF1A locus, FISH analysis of metaphase chromosomes (2) was performed using as probe a biotin-labeled 11-kb EcoRI fragment from the human HIF1A gene. The hybridization signal was restricted to a single D-group acrocentric chromosome (Fig. 2B). Digoxigenin-labeled probes specific for a-satellite DNA from chromosome 13 (D13Z1) or chromosome 15 (D15Z1) did not colocalize with the HIF1A signal (data not shown). In contrast, a digoxigenin-labeled YAC containing human genomic DNA previously mapped to chromosome 14q32 (D14S632) colocalized with the HIF1A signal on 24 of 31 metaphase spreads examined (Fig. 2B). These data confirm the results obtained by analysis of somatic cell hybrids and provide subchromosomal localization of HIF1A to the region encompassed by bands 14q21–q24 based upon the position of the HIF1A and D14S632 signals relative to the centromere. The human and mouse genes encoding the HIF-1a subunit of the transcription factor HIF-1 have been designated HIF1A (GDB Accession No. G00-512-229) and Hif1a (Accession Nos. MGD-CREX-495 and MGDCREX-496) by the Human and Mouse Genome Databases, respectively. In this study, we mapped the Hif1a locus to mouse chromosome 12, approximately 1.1 cM distal to the marker D12Bir3 and 1.1 cM proximal to the marker D12Mit3. These results localize Hif1a within a region of mouse chromosome 12, spanning a genetic distance of greater than 30 cM, that demonstrates conservation of synteny with a region of human chromosome 14 from 14q12 –q13 (PAX9) to 14q32.33 (IGHC) (1, 8). As predicted by these data, the HIF1A locus was assigned to human chromosome 14 based upon analysis of two different human 1 rodent somatic cell hybrid panels. Independent analysis by fluorescence in situ hybridization (FISH) confirmed the assignment and provided cytogenetic subchromosomal localization to the 14q21 –q24 region. Thus the genes HIF1A and ARNT, encoding the two subunits of HIF1, have been assigned to two different human chromosomes, 14q21–q24 and 1q21, respectively. Review of the Mouse Genome Database failed to reveal any mouse mutations that have been mapped in close proximity to Hif1a. In humans, the translocation t(12;14)(q13 –q15;q23– q24) has been identified in uterine leiomyomata (9). The 16 expressed sequence tags in the dbest database (as of December 1995) that have identity to the HIF-1a cDNA sequence (12) include a clone isolated from a uterus cDNA library (GenBank Accession No. T32012). Given the considerable number of neoplasia-specific translocations that involve genes encoding transcription factors (5), it may be of interest
gnmxal
AP: Genomics
439
SHORT COMMUNICATION
FIG. 2. Assignment of HIF1A to human chromosome 14. (A) PCR analysis of rodent 1 human monochromosomal hybrids for the presence of HIF1A sequences. DNA samples from somatic cell hybrids, each containing a unique human chromosome (1–22, X, Y), were assayed by PCR using HIF1A oligonucleotide primers that amplify a 129-bp DNA fragment from human genomic DNA (H). fx, HaeIII digestion of fx174 DNA. Arrow, 129-bp PCR product (lanes H and 14). (B) Localization of HIF1A to human chromosome 14q21 –q24. Two-probe, twocolor FISH analysis of human metaphase chromosomes was performed using a biotin-labeled HIF1A probe (green) and a digoxigenin-labeled YAC probe (D14S632) previously mapped to 14q32 (red). Chromosomes were counterstained with DAPI (purple).
to establish the position of the HIF1A locus relative to the leiomyoma-associated translocation breakpoint on chromosome 14. 5.
ACKNOWLEDGMENTS 6. We are grateful to Lucy Rowe and the Jackson Laboratory DNA Resource for assistance with interspecific backcross analysis; Sue Povey and Lois Maltais for human and mouse locus nomenclature assignment; and Roger Reeves for review of the manuscript. G.L.S. is an Established Investigator of the American Heart Association, and this work was supported by grants from the American Heart Association, the Lucille P. Markey Charitable Trust, and the National Institutes of Health (DK-39869).
7.
8.
REFERENCES 1. D’Eustachio, P. D. (1994). Mouse chromosome 12. Mamm. Genome 5(Suppl): S181–S195. 2. Geraghty, M. T., Kearns, W. G., Pearson, P. L., and Valle, D. (1993). Isolation and characterization of an ornithine aminotransferase-related sequence (OATL3) mapping to 10q26. Genomics 17: 510–513. 3. Hoffman, E. C., Reyes, H., Chu, F.-F., Sander, F., Conley, L. H., Brooks, B. A., and Hankinson, O. (1991). Cloning of a factor required for activity of the Ah (dioxin) receptor. Science 252: 954–958. 4. Johnson, B., Brooks, B. A., Heinzmann, C., Diep, A., Mohandas, T., Sparkes, R. S., Reyes, H., Hoffman, E., Lange, E., Gatti,
AID Genom 4115
/
6r16$$$521
05-16-96 00:13:19
9.
10.
11. 12.
R. A., Xia, Y.-R., Lusis, A. J., and Hankinson, O. (1993). The Ah receptor nuclear translocator gene (ARNT) is located on q21 of human chromosome 1 and on mouse chromosome 3 near Cf3. Genomics 17: 592–598. Rabbitts, T. H. (1994). Chromosomal translocations in human cancer. Nature 372: 143–149. Rowe, L. B., Nadeau, J. H., Turner, R., Frankel, W. R., Letts, V. A., Eppig, J. T., Ko, M. S. H., Thurston, S. J., and Birkenmeier, E. H. (1994). Maps from two interspecific backcross DNA panels available as a community genetic mapping resource. Mamm. Genome 5: 253–274. Semenza, G. L. (1994). Regulation of erythropoietin production: New insights into molecular mechanisms of oxygen homeostasis. Hematol. Oncol. Clin. N. Am. 8: 863 –884. Stapleton, P., Weith, A., Urbanek, P., Koznik, Z., and Busslinger, M. (1993). Chromosomal localization of seven PAX genes and cloning of a novel family member, PAX-9. Nat. Genet. 3: 292– 298. Trent, J. M., Kaneko, Y., and Mitelman, F. (1989). Report of the committee on structural chromosome changes in neoplasia. Cytogenet. Cell Genet. 51: 533– 562. Wang, G. L., and Semenza, G. L. (1995). Purification and characterization of hypoxia-inducible factor 1. J. Biol. Chem. 270: 1230 –1237. Wang, G. L., and Semenza, G. L. (1996). Oxygen sensing and response to hypoxia by mammalian cells. Redox Rep. 2: 89–96. Wang, G. L., Jiang, B.-H., Rue, E. A., and Semenza, G. L. (1995). Hypoxia-inducible factor 1 is a basic – helix– loop –helix –PAS heterodimer regulated by cellular O 2 tension. Proc. Natl. Acad. Sci. USA 92: 5510 –5514.
gnmxal
AP: Genomics