The coupling of epigenome replication with DNA replication

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The coupling of epigenome replication with DNA replication Qian Liu1 and Zhizhong Gong1,2,3 In multicellular organisms, each cell contains the same DNA sequence, but with different epigenetic information that determines the cell specificity. Semi-conservative DNA replication faithfully copies the parental nucleotide sequence into two DNA daughter strands during each cell cycle. At the same time, epigenetic marks such as DNA methylation and histone modifications are either precisely transmitted to the daughter cells or dynamically changed during S-phase. Recent studies indicate that in each cell cycle, many DNA replication related proteins are involved in not only genomic but also epigenomic replication. Histone modification proteins, chromatin remodeling proteins, histone variants, and RNAs participate in the epigenomic replication during S-phase. As a consequence, epigenome replication is closely linked with DNA replication during S-phase. Addresses 1 State Key Laboratory of Plant Physiology and Biochemistry, College of Biological Sciences, China Agricultural University, Beijing, 100193, China 2 China Agricultural University-University of California-Riverside Center for Biological Sciences and Biotechnology, Beijing, 100193, China 3 National Center for Plant Gene Research, Beijing, 100193, China Corresponding author: Gong, Zhizhong ([email protected])

Current Opinion in Plant Biology 2011, 14:187–194 This review comes from a themed issue on Genome studies and molecular genetics Edited by Jeffrey L. Bennetzen and Jian–Kang Zhu Available online 11th January 2011 1369-5266/$ – see front matter # 2010 Elsevier Ltd. All rights reserved. DOI 10.1016/j.pbi.2010.12.001

Introduction Although each cell of multicellular organisms maintains identical DNA sequences after each cell division during development, different types of cells exhibit different gene expression patterns that are determined by epigenetical marks. These epigenetical marks include DNA methylation, histone modifications, histone variants, chromatin structures, and noncoding RNAs. Each cell reads different epigenetic marks precisely during different developmental stages or in response to different environmental stresses. Establishment of epigenetic marks is partially mediated by noncoding RNAs, which are conserved in animals, plants, and yeasts [1]. Once these epigenetic marks are established, epigenetic inheritance will guarantee the transmission of these www.sciencedirect.com

marks in each cell cycle and even from generation to generation. Genomic regions with epigenetic marks can be distinguished by highly condensed heterochromatin that is localized in transposons, repetitive sequences, centromeric regions, and telomeres. Heterochromatin in plants is usually characterized by histone marks such as histone 3 lysine 9 mono/dimethylation, 27 mono/dimethylation, and histone 4 lysine 20 monomethylation [2]. Decondensed euchromatin that is localized in the gene-rich regions is usually modified by histone marks such as H3K4me3 and hyperacetylated histone [2]. Unlike DNA replication, however, epigenomic replication does not always precisely copy all the parental epigenetic marks in every cell cycle, which results in epigenomic changes that lead to various cell types (called cell differentiation during development) or to different cell responses to environmental stresses. In this review, we will summarize researches concerning the coupling of epigenetic inheritance with DNA replication.

Disruption of chromatin structures in preparation for DNA replication DNA replication can be divided into four stages including pre-replication, initial replication, replication elongation, and maturation [3]. DNA replication machinery is highly conserved among eukaryotes. Euchromatic regions replicate early while heterochromatin regions replicate late in the S-phase, suggesting that loose chromatin structures are more easily opened than condensed chromatin structures for DNA replication [4]. The origin recognition complex (ORC) binds onto the origin sites of replication and sequentially recruits Cdc6 and Cdt1, which leads to the assembly of the mini-chromosome maintenance complex 2-7 (MCM2-7, a ring-shaped, heterohexameric AAA + ATPase) onto chromatin [5]. Disruption of parental nucleosomes is required for the formation of replication forks and for the synthesis of daughter strands because chromatin renders the DNA template structurally inaccessible. It is clear that ATP-dependent chromatin remodeling enzymes and chaperone proteins are required during this process. In mammalian cells, the Williams syndrome transcription factor interacts with the DNA clamp proliferating cell nuclear antigen (PCNA, a ring shaped homotrimer) and recruits ISWI chromatin remodeling ATPase protein SNF2H to the replication sites [6]. Another homolog, ACF1-ISWI, is required for DNA replication through heterochromatin [7]. The Swi2/ Snf2 chromatin remodeling protein INO80 is recruited to the replication origins, and is responsible for replication fork stability and restarting replication under replication Current Opinion in Plant Biology 2011, 14:187–194

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stress [8]. In Arabidopsis, INO80 positively regulates homologous recombination and DNA repair [9]. These results indicate that chromatin remodeling factors are required to open the chromatin structure. Histone acetyltransferase HBO1 acetylates H4. ORC1 and MCM2 directly interact with HBO1, which is required for the binding of MCM2-7 to chromatin [10]. Histone deacetylase Sir2 in budding yeast and RPD3 in fission yeast or Drosophila negatively regulate the prereplication assembly/origin firing [11,12]. Plant ORC1 has a specific PHD domain that binds to H3k4me3 (a histone mark associating with transcriptional activation) [13]. Given the similarity of chromatin changes during DNA replication and transcription, H3K4me3 modification, like H4 acetylation, might also occur near DNA replication origins. The histone chaperone FACT (which facilitates chromatin transcription and consists of two subunits) interacts with MCMs in the replication origins to mediate chromatin loosening and to facilitate chromatin unwinding by the MCM complex [14]. In Arabidopsis, two FACT subunits are co-localized in the euchromatin regions with actively transcribed genes [15]. As mentioned above, these FACTs might also function in DNA replication origins. Overall, research in this area indicates that for DNA replication to proceed, chromatin must be loosened by dynamic epigenetic modifications.

Nucleosome assembly during the process of DNA replication The Cdc45, GINS (go ichi ni san), and the MCM holocomplex are needed to unwind DNA strands at the replication fork [16]. Then various DNA replicationrelated proteins, including DNA replication protein A (for binding single-strand), DNA polymerase a-primase (for synthesizing a short RNA and DNA), DNA replication factor C (for recruiting PCNA), PCNA, DNA polymerase e (for lagging strand synthesis), and DNA polymerase d (for leading strand synthesis), are loaded onto the replication machinery for daughter-strand synthesis during S-phase (Figure 1) [17]. During this process, the original nucleosomes from parental strands must be restored in the newly synthesized hybrid strands in order to transmit the epigenetic information [18]. Two models have been used to explain the nucleosome reassembly after DNA replication: the H3–H4 tetramer splits into two H3–H4 dimers, which are used as templates for nucleosome assembly, and the old intact H3–H4 tetramers act as templates for the synthesis of neighboring and new H3–H4 dimer [18]. Recently, Xu et al. reported that most H3.1–H4 tetramers remained intact during the DNA replication-dependent nucleosome deposition, and that these tetramers are used as templates for copying their modifications onto neighboring, newly synthesized histones within large heterochromatic regions [19]. The H3.3–H4 tetramer, however, is split. H3.1 is a replicative histone variant that is incorporated into duplicated chroCurrent Opinion in Plant Biology 2011, 14:187–194

matin during DNA replication, whereas H3.3 (and other histone variants) is a replacement variant that can be incorporated into chromatin independent of DNA replication. The significance of the split feature in the H3.1/ H3.3 mixing regions is not yet known [19]. Both models probably operate during nucleosome reassembly in DNA replication [18]. Chromatin-Assembly Factor-1 (CAF-1), a conserved three-subunit protein in eukaryotic organisms, is recruited to the DNA replication sites by PCNA and preferentially deposits the new H3–H4 (in dimer form after synthesizing) onto replication DNA [20]. CAF1 also interacts with heterochromatin protein1 (HP1) to ensure heterochromatin transfer at the replication fork [21]. In Arabidopsis, three CAF-1 subunits are encoded by FASCIATA1 (FAS1, encoding larger subunit), FAS2 (encoding middle subunit), and MULTICOPY SUPPRESSOR OF IRA1 (MSI1, encoding small subunit) [22]. Mutations in FAS1, FAS2, or MSI1 result in various developmental defects, reduce the amounts of heterochromatin, lead to the release of transcriptional gene silencing (TGS) in some loci, and increase homologous recombination, but do not have a clear effect on DNA methylation [23,24,25]. FAS1 and FAS2 are also found to maintain telomere length and copy number of 45S rDNA [26]. MGOUN1 encodes a type IB DNA topoisomerase in Arabidopsis that might have a role in chromatin assembly. MGOUN1 works synergistically with FAS and other chromatin remodeling proteins such as PICKLE to regulate the silenced genes such as AGAMOUS during plant development [27]. MSI1 is one cocomponent of three Polycomb-Group repressor complexes that include the VERNALIZATION (VRN), the EMBRYONIC FLOWER (EMF), and the FERTILIZATION INDEPENDENT SEED (FIS). These repressor complexes epigenetically mediate TGS of various target genes [28]. It is therefore possible that CAF-1 facilitates the incorporation of histones into chromatin during DNA replication in plants. Anti-silencing function protein 1 (ASF1) is another histone chaperon that cooperates with CAF-1 to incorporate the newly synthesized H3–H4 onto chromatin during DNA replication [29,30]. ASF1 is a substrate of TOUSLED-like protein kinase that functions in the chromatin assembly pathway [31]. TOUSLED was originally isolated from Arabidopsis and is conserved in animals. Mutations in TOUSLED protein kinase lead to developmental defects and release of TGS without changing DNA methylation in Arabidopsis [32]. NUCLEOSOME ASSEMBLY PROTEIN1 (NAP1) and NAP2 chaperon H2A/H2B for chromatin assembly during DNA replication. The double mutant nap1 nap2 results in defects in root development and the releasing of TGS [33] (Table 1).

Inheritance of histone modifications and DNA methylation during DNA replication Inheritance of various histone modifications is mediated by different proteins, most of which are associated with www.sciencedirect.com

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Figure 1

TOUSLED La gg in

ASF1

MBD

FAS1

tra

nd

RFC1 PCNA

VIM1

ATXR5/6

Pol α

ROS1

MCM8

MC M1

0

SET1

TEBICHI

LH P1

se

MET1

Pr im a

gs

Pol δ

2 RPA

DDM1

ASF1

CDC54

MCM9

MCM2-7

BRU1 Pol ε

GINS

nd

tra

s ing

ad

Le

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Proteins involved in the coupling of epigenomic replication with DNA replication in S-phase (modified from [3]). Semi-conservative DNA replication occurs on the leading strand synthesized by DNA Pol e and on the lagging strand synthesized by Pol d. In the DNA replication fork, the core DNA replication proteins and their interacting proteins work together to maintain DNA methylation, histone modifications, and chromatin structures. ASF1 (ANTI-SILENCING FACTOR 1) may interact with MCM2-7. ROS1 (a DNA demethylation enzyme) interacts with RPA2A. Pol a interacts with LHP1 (LIKE-HETEROCHROMATIN PROTEIN 1). PCNA (proliferating cell nuclear antigen) could interact with different proteins by the same domain at different replication times as in other organisms. These proteins include ATXR5/6 (For H3K27me1), LHP1, RFC1, FAS1 (one of CHROMATIN ASSEMBLY FACTOR-1 subunits), VIM1 (VARIANT IN METHYLATION 1), MET1 (DNA METHYLTRANSFERASE 1), and MCM10. However, most of PCNA interaction partners in plants have not been confirmed. FAS1 may interact with MBD (DNA methyl-binding domain protein) and ASF1. ASF1 also interacts with TOUSLED protein kinase. VIM1 interacts with MET1 and SET1 (H3K9 methyltransferase). DDM1 (DECREASED DNA METHYLATION 1) probably interacts with MCM10 (Wang and Gong, unpublished results). BRU1 and TEBICHI are involved in this process, but their relationship with other DNA replication proteins is not known. For information about the core replication proteins in plants, please see Scheltz et al., 2007 [3].

DNA replication-related proteins. DNA polymerase a interacts with HP1 in yeasts or animals, or with likeheterochromatin protein 1 (LHP1) in Arabidopsis [34]. Human ORC1p also interacts with HP1 [35]. HP1 is a crucial heterochromatin-associated protein responsible for creating a repressed status in its recruited genomic region in fungi and animals, but also functions in positive regulation of gene expression [36]. Like HP1, LHP1 from Arabidopsis has roles in regulating both heterochromatin and euchromatin [37,38]. Mutations in either ORC1 in yeast or DNA polymerase a in yeast or Arabidopsis result in the release of TGS, suggesting that ORC1 and DNA polymerase a are crucial in maintaining TGS [39,40]. DNA replication protein A 2A (a single strand-binding protein) interacts with REPRESSOR of SILENCING1, a DNA demethylation enzyme first identified in Arabidopsis [41,42]. ROS1 functions in two transgenes (pRD29ALUC and p35S-NPTII) located in one T-DNA locus via www.sciencedirect.com

two different regulation mechanisms [40,41,42,43]. ros1 mutation silences the original activated pRD29A-LUC by a mechanism that is dependent on the RNA-directed DNA methylation (RdDM) pathway, but silences the original activated p35S-NPTII by a mechanism that is independent of the RdDM pathway. That ROS1 interacts with RPA2A suggests that DNA methylation is dynamically maintained during DNA replication [41,42]. Mutations in RPA2A, Replication Factor C1 (RFC1) [43], DNA polymerase e [44], BRU1 [25], TEBICHI (containing helicase and DNA polymerase domains) [45], and RNR2 (Ribonucleotide Reductase2, catalyzing a rate-limiting step in the production of deoxyribonucleotides) [46] all lead to the release of TGS on some loci in Arabidopsis, indicating that most of the core DNA-replication proteins and DNA replication-related proteins are directly involved in transcriptional gene silencing/chromatin maintenance. Current Opinion in Plant Biology 2011, 14:187–194

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Table 1 DNA replication and epigenomic replication factors discussed in this review Gene

AGI number

Protein

DNA replication Cdc45 GINS

At3g25100 At1g80190

Components of the active DNA replication fork Components of the active DNA replication fork

ORC1A ORC1B MCM2 MCM3 MCM4 MCM5 MCM6 MCM7 ICU2 ABO4 EMB2780 RPA2A RFC1 PCNA1 PCNA2 TEBICHI BRU1

At3g12530 At4g14700 At4g12620 At1g44900 At5g46280 At2g16440 At2g07690 At5g44635 At4g02060 At5g67100 At1g08260 At5g63960 At2g24490 At5g22010 At1g07370 At2g29570 At4g32700 At3g18730

Components of The origin recognition complex Involved in the initiation of DNA replication

RNR2 FEN TSL

At3g23580 At5g26680 At5g20930

Function Replication initiation Replication initiation; DNA polymerase epsilon processivity factor Origin recognition

DNA helicase DNA helicase DNA helicase DNA helicase DNA helicase DNA helicase Catalytic subunit Subunit of DNA polymerase a Catalytic subunit Subunit of DNA polymerase e Subunit of DNA polymerase d Subunit of RPA complex DNA-dependent ATPase DNA polymerase clamp

Unwind DNA strands Unwind DNA strands Unwind DNA strands Unwind DNA strands Unwind DNA strands Unwind DNA strands DNA primer synthesis Lagging strand synthesis Leading strand synthesis Single strand DNA binding PCNA loading Stimulate DNA polymerase

Containing helicase and DNA polymerase domains Nuclear protein with two predicted protein–protein interaction domains Ribonucleotide Reductase Flap nuclease1 TOUSLED-like kinases

Unknown Unknown

Epigenetic modification DRM2 At5g14620

Cytosine methyltransferase

MET1 ROS1 DEMETER DML2 DML3 VIM1 LHP1

At5g49160 At2g36490 At5g04560 At3g10010 At4g34060 At1g57820 At5g17690

Cytosine methyltransferase DNA Glycosylase/Lyase DNA Glycosylase DNA Glycosylase DNA Glycosylase Methylcytosine-binding protein Like heterochromatin protein 1

ATXR1 ATXR2 ATXR7 ATXR5 ATXR6 LSD1/LDL1 LDL2

At1g26760 At3g21820 At5g42400 At5g09790 At5g24330 At1g62830 At3g13682

A trithorax class H3K4 methylase A Set1 class H3K4 methylase A Set1 class H3K4 methylase A Set1 class Histone methylase A Set1 class Histone methylase Lysine-Specific Histone Demethylase Lysine-Specific Demethylase1–like1

De novo methylation and maintaining non-CG methylation Maintaining CG methylation DNA demethylation DNA demethylation DNA demethylation DNA demethylation DNA binding and chromatin binding Regulate both heterochromatin and euchromatin Maintaining H3K4 methylation Maintaining H3K4 methylation Maintaining H3K4 methylation H3K27 monomethyltransferases H3K27 monomethyltransferases Demethylation of H3K4me2 Demethylation of histone

Chromatin assembly H3.1 At1g13370

Histone variant

H3.3

At1g19890

Histone variant

FACT complex

Histone chaperone

INO80 NAP1

At3g28730 At4g10710 At3g57300 At2g35110

NAP2 FAS1 FAS2 MSI1 ASF1 MGOUN1 PICKLE DDM1

At5g44110 At1g65470 At5g64630 At5g58230 At1g66740 At5g55300 At2g25170 At5g66750

Nucleosome assembly protein Larger subunit of CAF-1 Middle subunit of CAF-1 Small subunit of CAF-1 Histone chaperone type IB DNA topoisomerase Swi/Swf ATPase Swi2/Snf2 ATPase

Swi2/Snf2 ATPase Nucleosome assembly protein

Current Opinion in Plant Biology 2011, 14:187–194

dNTPs biosynthesis Cleave the RNA/DNA flap Unknown

DNA replication-dependent nucleosome deposition DNA replication-independent nucleosome deposition Facilitate chromatin transcription Chromatin remodeling Chaperon H2A/H2B for chromatin assembly during DNA replication Deposits the new H3–H4 onto replication DNA Deposits the new H3–H4 onto replication DNA Deposits the new H3–H4 onto replication DNA Chromatin assembly Chromatin assembly Chromatin remodeling Chromatin remodeling

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PCNA is assisted by RFC ATPase to be opened and closed around the DNA. PCNA is considered a main landing pad on the replication fork for recruitment of various chromatin modifiers through the same interaction domain at different periods of DNA replication [17]. Arabidopsis contains two copies of PCNA, but genetic study of PCNA has not been performed, and little information is available on plant PCNA [47]. Because PCNA is highly conserved among different eukaryotic organisms, its biological functions might be similar. Numerous reports indicate that PCNA plays diverse roles in nucleosome assembly, DNA methylation, histone deacetylation, histone methylation, and chromatin remodeling [18]. In mammals, PCNA recruits DNMT1 (DNA methylation maintaining methyltransferase, a plant homolog of DNA methyltransferase1 (MET1) to the replication site for maintaining DNA CG methylation [48]. UHRF1/ NP95, a ubiquitin-like protein containing PHD and RING finger domains 1 and a homolog of the VARIANT IN METHYLATION (VIM1) in Arabidopsis [49], specifically binds to hemimethylated CG dinucleotides and recruits DNMT1 for facilitating faithful maintenance of DNA methylation during DNA replication [50–52]. VIM1 also interacts with tobacco NtSET1, a SRA-SET domain containing H3K9 methyltransferase protein. NtSET1 probably plays a role in reinforcing the H3K9 and DNA methylation in the heterochromatin region [53]. In animals, PCNA interacts with and recruits different histone methyltransferases including SUV39H for H3K9me3 and SET8 for H4K20me1 [18] in the heterochromatin regions. Recently, the genes ARABIDOPSIS TRITHORAX-RELATED PROTEIN 5 (ATXR5) and ATXR6 were found to encode H3K27 monomethyltransferases that interact with PCNA, suggesting a key role of ATXR5/6 in maintaining H3K27me1 during DNA replication in Arabidopsis [47,54]. The atxr5 atxr6 double mutant shows decondensed heterochromatin and release of TGS [54], and causes over replication [55], indicating that heterochromatic DNA replication is regulated by H3K27 methytransferases.

Rebuilding new chromatin structure during DNA replication Epigenomic replication not only transfers the epigenetic marks to the daughter cells but also creates new epigenetic marks during the S-phase; these new epigenetic marks will lead to cell differentiation or unscheduled changes [18]. In higher plants, two specific RNA polymerases, Pol IV and Pol V, together with Pol II and other RNA interference proteins produce siRNA and long noncoding RNAs to guide de novo DNA methylation (catalyzed by DRM2 DNA methyltransferase) and heterochromatin formation in the repetitive regions and in transposons [56]. In Arabidopsis, three main polycombrelated repressor complexes (the VRN, the EMF, and the FIS) regulate the different developmental processes by setting up H3K27me3 in the targeted loci to silence the www.sciencedirect.com

target gene expression [28]. Recent studies on FLOWERING LOCUS C (FLC) expression indicate that cold stressinduced anti-sense RNAs in the 30 region of the FLC suppress sense FLC expression. These anti-sense RNAs probably recruit the polycomb machinery to the FLC locus to initiate and maintain heterochromatin in Arabidopsis [57,58]. A similar study suggests that the long noncoding RNA HOTAIR serves as a scaffold that tethers both Polycomb Repressive Complex 2 and LSD1/CoREST/REST complex (LSD1 for demethylation of H3K4me2) and thereby positions the specific chromatin on the target genes [59]. The Polycomb-Group complexes can be antagonistically mediated by Trithoraxrelated proteins in Arabidopsis. ARABIDOPSIS TRITHORAX1 (ATX1, a Trithorax class H3K4 methylase), ATX2, and ARABIDOPSIS TRITHORAXRELATED7 (ATXR7, a Set1 class H3K4 methylase) modify the H3K4me at FLC chromatin to dynamically regulate FLC expression [2]. Under certain environmental conditions/developmental stages, DNA methylation and histone modifications can be actively removed by proteins such as the DNA demethylation protein ROS1 and its related homologs DEMETER and DEMETERlike 2 and DEMETER-like 3 [60,61], or the histone demethylation JmiC domain proteins and Lysine-Specific Demethylase1–like1(LDL1)/LDL2 proteins [2]. Once these new epigenetic marks are created during development or under environmental stress conditions, epigenomic replication mechanisms will guarantee their transmission in each cell cycle.

Perspectives Not all chromatin modifications are coupled with DNA replication for mitotic inheritance. Some chromatin marks, such as histone variants, are changed independently of the DNA replication process. In animals, long noncoding RNAs have been found to participate in regulating the expression of numerous genes including X-inactivation, imprinting, and polycomb silencing genes [62]. In plants, siRNA and the long noncoding RNA-dependent DNA methylation pathway have been well studied [56]. Except for the roles of long noncoding RNAs in the RdDM pathway and in the VRN complex for controlling FLC expression, however, we have little information on the functions of long noncoding RNAs in regulating the expression of other genes in plants. Although we have confirmed that many DNA replication proteins participate in both DNA and chromatin replication, the mechanisms of how these proteins work are not well known. Whether long/small noncoding RNAs participate in the coupling of DNA replication with epigenomic replication requires further study. Many DNA replication related proteins, such as BRU1, CAF-1, Tousled protein kinase, and several DNA replication polymerases are found to be necessary for maintaining epigenetic silencing, but probably not participate in DNA methylation control, suggesting that Current Opinion in Plant Biology 2011, 14:187–194

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DNA methylation and other epigenetic modifications are transmitted in different mechanisms during DNA replication. Besides the genetic systems used for dissecting the RdDM pathway and Polycomb-Group complexes in Arabidopsis, other new systems are needed to analyze the mechanisms of DNA/epigenomic replication. In contrast to heterochromatin replication, euchromatin replication in each cell cycle is poorly understood and requires more attention. The plastids in plant cells may also contribute to epigenomic replication. CUE1 encodes a plastid inner envelope phosphoenolpyruvate/phosphate translocator. In the cue1 mutant, TGS is released, suggesting that the retrograde signals from the plastid can be transduced to regulate TGS in the nucleus [63]. Whether and how this process is related to DNA/epigenomic replication requires study.

Acknowledgement Our work was supported by the National Nature Science Foundation of China.

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27. Graf P, Dolzblasz A, Wurschum T, Lenhard M, Pfreundt U, Laux T:  MGOUN1 encodes an Arabidopsis type IB DNA topoisomerase required in stem cell regulation and to maintain developmentally regulated gene silencing. Plant Cell 2010, 22:716-728. Topoisomerases transiently break one or both DNA strands to solve the topological problems, and are required for chromatin assembly during DNA replication. In this study, the authors found that together with other chromatin remodeling components, MEOUN1 is required for stabilizing epigenetic states of some regulated genes. 28. Schatlowski N, Creasey K, Goodrich J, Schubert D: Keeping plants in shape: polycomb-group genes and histone methylation. Semin Cell Dev Biol 2008, 19:547-553. 29. Natsume R, Eitoku M, Akai Y, Sano N, Horikoshi M, Senda T: Structure and function of the histone chaperone CIA/ASF1 complexed with histones H3 and H4. Nature 2007, 446:338-341. 30. Groth A, Corpet A, Cook AJ, Roche D, Bartek J, Lukas J, Almouzni G: Regulation of replication fork progression through histone supply and demand. Science 2007, 318:1928-1931. 31. Sillje HH, Nigg EA: Identification of human Asf1 chromatin assembly factors as substrates of Tousled-like kinases. Curr Biol 2001, 11:1068-1073. 32. Wang Y, Liu J, Xia R, Wang J, Shen J, Cao R, Hong X, Zhu JK, Gong Z: The protein kinase TOUSLED is required for maintenance of transcriptional gene silencing in Arabidopsis. EMBO Rep 2007, 8:77-83. 33. Zhu Y, Dong A, Meyer D, Pichon O, Renou JP, Cao K, Shen WH: Arabidopsis NRP1 and NRP2 encode histone chaperones and are required for maintaining postembryonic root growth. Plant Cell 2006, 18:2879-2892. 34. Barrero JM, Gonzalez-Bayon R, del Pozo JC, Ponce MR, Micol JL: INCURVATA2 encodes the catalytic subunit of DNA Polymerase alpha and interacts with genes involved in chromatin-mediated cellular memory in Arabidopsis thaliana. Plant Cell 2007, 19:2822-2838. 35. Lidonnici MR, Rossi R, Paixao S, Mendoza-Maldonado R, Paolinelli R, Arcangeli C, Giacca M, Biamonti G, Montecucco A: Subnuclear distribution of the largest subunit of the human origin recognition complex during the cell cycle. J Cell Sci 2004, 117:5221-5231. 36. Fanti L, Pimpinelli S: HP1: a functionally multifaceted protein. Curr Opin Genet Dev 2008, 18:169-174. 37. Mylne JS, Barrett L, Tessadori F, Mesnage S, Johnson L, Bernatavichute YV, Jacobsen SE, Fransz P, Dean C: LHP1, the Arabidopsis homologue of HETEROCHROMATIN PROTEIN1, is required for epigenetic silencing of FLC. Proc Natl Acad Sci USA 2006, 103:5012-5017. 38. Libault M, Tessadori F, Germann S, Snijder B, Fransz P, Gaudin V: The Arabidopsis LHP1 protein is a component of euchromatin. Planta 2005, 222:910-925. 39. Fox CA, Ehrenhofer-Murray AE, Loo S, Rine J: The origin recognition complex, SIR1, and the S phase requirement for silencing. Science 1997, 276:1547-1551. 40. Liu J, Ren X, Yin H, Wang Y, Xia R, Wang Y, Gong Z: Mutation in  the catalytic subunit of DNA polymerase alpha influences transcriptional gene silencing and homologous recombination in Arabidopsis. Plant J 2010, 61:36-45. This paper together with [34] provides evidence to indicate that the DNA polymerase alpha is involved in chromatin-mediated inheritance during DNA replication. DNA polymerase alpha physically interacts with Like Heterochromatin Protein1 (LHP1) [34], the homolog of Heterochromatin Protein1 (HP1) in animal and yeast, which is needed for epigenetic inheritance during DNA replication in the S-phase. 41. Kapoor A, Agarwal M, Andreucci A, Zheng X, Gong Z, Hasegawa PM, Bressan RA, Zhu JK: Mutations in a conserved replication protein suppress transcriptional gene silencing in a DNA-methylation-independent manner in Arabidopsis. Curr Biol 2005, 15:1912-1918. 42. Xia R, Wang J, Liu C, Wang Y, Wang Y, Zhai J, Liu J, Hong X, Cao X, Zhu JK et al.: ROR1/RPA2A, a putative replication protein A2, functions in epigenetic gene silencing and in regulation of www.sciencedirect.com

meristem development in Arabidopsis. Plant Cell 2006, 18:85-103. 43. Liu Q, Wang J, Miki D, Xia R, Yu W, He J, Zheng Z, Zhu JK, Gong Z:  DNA replication factor C1 mediates genomic stability and transcriptional gene silencing in Arabidopsis. Plant Cell 2010, 22:2336-2352. ROS1 is a first identified DNA demethylation protein in higher eukaryotes. Mutations in ROS1 lead to hypermethylated DNA in a stress inducible promoter RD29A and silence the originally activated pRD29A-LUC and its linked p35S-NPTII with different mechanisms (RdDM pathway for RD29A-LUC, but RdDM independent pathway for p35S-NPTII). The authors identified RFC1 as a repressor of silenced 35S-NTPII. This research provides some interesting data to show that ROS1 negatively controls telomere length. They also indicate that the core DNA replication proteins such as RFC1, DNA polymerase alpha, DNA polymerase epsilon, replication protein A2A are involved in positively regulating telomere length. 44. Yin H, Zhang X, Liu J, Wang Y, He J, Yang T, Hong X, Yang Q,  Gong Z: Epigenetic regulation, somatic homologous recombination, and abscisic acid signaling are influenced by DNA polymerase epsilon mutation in Arabidopsis. Plant Cell 2009, 21:386-402. This paper reports a DNA polymerase epsilon participating in epigenetic inheritance without affecting DNA methylation in Arabidopsis. The paper also points out the importance of DNA replication proteins in ABA regulation of plant growth. 45. Inagaki S, Nakamura K, Morikami A: A link among DNA replication, recombination, and gene expression revealed by genetic and genomic analysis of TEBICHI gene of Arabidopsis thaliana. PLoS Genet 2009, 5:e1000613. 46. Wang C, Liu Z: Arabidopsis ribonucleotide reductases are critical for cell cycle progression. DNA damage repair, and plant development. Plant Cell 2006, 18:350-365. 47. Raynaud C, Sozzani R, Glab N, Domenichini S, Perennes C, Cella R, Kondorosi E, Bergounioux C: Two cell-cycle regulated SET-domain proteins interact with proliferating cell nuclear antigen (PCNA) in Arabidopsis. Plant J 2006, 47:395-407. 48. Chuang LS, Ian HI, Koh TW, Ng HH, Xu G, Li BF: Human DNA(cytosine-5) methyltransferase-PCNA complex as a target for p21WAF1. Science 1997, 277:1996-2000. 49. Woo HR, Pontes O, Pikaard CS, Richards EJ: VIM1, a methylcytosine-binding protein required for centromeric heterochromatinization. Genes Dev 2007, 21:267-277. 50. Arita K, Ariyoshi M, Tochio H, Nakamura Y, Shirakawa M: Recognition of hemi-methylated DNA by the SRA protein UHRF1 by a base-flipping mechanism. Nature 2008, 455:818-821. 51. Sharif J, Muto M, Takebayashi S, Suetake I, Iwamatsu A, Endo TA, Shinga J, Mizutani-Koseki Y, Toyoda T, Okamura K et al.: The SRA protein Np95 mediates epigenetic inheritance by recruiting Dnmt1 to methylated DNA. Nature 2007, 450:908-912. 52. Bostick M, Kim JK, Esteve PO, Clark A, Pradhan S, Jacobsen SE: UHRF1 plays a role in maintaining DNA methylation in mammalian cells. Science 2007, 317:1760-1764. 53. Liu S, Yu Y, Ruan Y, Meyer D, Wolff M, Xu L, Wang N, Steinmetz A, Shen WH: Plant SET- and RING-associated domain proteins in heterochromatinization. Plant J 2007, 52:914-926. 54. Jacob Y, Feng S, LeBlanc CA, Bernatavichute YV, Stroud H,  Cokus S, Johnson LM, Pellegrini M, Jacobsen SE, Michaels SD: ATXR5 and ATXR6 are H3K27 monomethyltransferases required for chromatin structure and gene silencing. Nat Struct Mol Biol 2009, 16:763-768. PCNA is a sliding clamp that interacts with various DNA replication related proteins. Two set domain proteins ATXR5 and ATXR6 with H3K27 monomethyltransferase activity interact with PCNA. atxr5 atxr6 double mutants reduce H3K27me1 and release transcriptional gene silencing without changing H3K9me2 and DNA methylation. This study represents a novel pathway for H3K27me1 in transcriptional repression in Arabidopsis. 55. Jacob Y, Stroud H, Leblanc C, Feng S, Zhou L, Caro E, Hassel C,  Gutierrez C, Michaels SD, Jacobsen SE: Regulation of heterochromatic DNA replication by histone H3 lysine 27 methyltransferases. Nature 2010, 466:987-991. Current Opinion in Plant Biology 2011, 14:187–194

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This study indicates that ATXR5 and ATXR6 are responsible for regulating heterochromatin DNA replication. atxr5 atxr6 double mutants increase the re-replication of the transposons and repetitive regions in the genome. It is a novel pathway that ATXR5 and ATXR6 prevent re-replication of heterochromatin in Arabidopsis. 56. Law JA, Jacobsen SE: Establishing, maintaining and modifying  DNA methylation patterns in plants and animals. Nat Rev Genet 2010, 11:204-220. This is a good review paper that compares the DNA methylation between animals and plants. 0

57. Liu F, Marquardt S, Lister C, Swiezewski S, Dean C: Targeted 3  processing of antisense transcripts triggers Arabidopsis FLC chromatin silencing. Science 2010, 327:94-97. Please see [58]. 58. Swiezewski S, Liu F, Magusin A, Dean C: Cold-induced silencing  by long antisense transcripts of an Arabidopsis Polycomb target. Nature 2009, 462:799-802. Long noncoding antisense RNAs are important for regulating gene expression in animals. Although a lot of antisense RNAs are found in the transcriptional files in Arabidopsis, their biological functions are not well studied yet. In [57] and [58], the authors identify cold inducible antisense RNAs in FLC locus. These antisense RNAs probably play a role in recruiting Polycomb proteins and initiating the formation of heterochromatin in the FLC. This is the first example that an antisense RNA triggers the silencing of its target gene in Arabidopsis. It is might be a common mechanism in plants for controlling the expression of the corresponding genes.

Current Opinion in Plant Biology 2011, 14:187–194

59. Tsai MC, Manor O, Wan Y, Mosammaparast N, Wang JK, Lan F, Shi Y, Segal E, Chang HY: Long noncoding RNA as modular scaffold of histone modification complexes. Science 2010, 329:689-693. 60. Gehring M, Huh JH, Hsieh TF, Penterman J, Choi Y, Harada JJ, Goldberg RB, Fischer RL: DEMETER DNA glycosylase establishes MEDEA polycomb gene self-imprinting by allelespecific demethylation. Cell 2006, 124:495-506. 61. Gong Z, Morales-Ruiz T, Ariza RR, Roldan-Arjona T, David L, Zhu JK: ROS1, a repressor of transcriptional gene silencing in Arabidopsis, encodes a DNA glycosylase/lyase. Cell 2002, 111:803-814. 62. Wilusz JE, Sunwoo H, Spector DL: Long noncoding RNAs: functional surprises from the RNA world. Genes Dev 2009, 23:1494-1504. 63. Shen J, Ren X, Cao R, Liu J, Gong Z: Transcriptional  gene silencing mediated by a plastid inner envelope phosphoenolpyruvate/phosphate translocator CUE1 in Arabidopsis. Plant Physiol 2009, 150:1990-1996. The authors identified a chloroplast inner membrane protein CUE1 that releases transcriptional gene silencing of nuclear genes when mutated. The results suggest that retrograde signals from chloroplast participate in controlling TGS in nucleus.

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