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. 2011 May 1;6(5):552–559. doi: 10.4161/epi.6.5.15082

Nucleosomes in the neighborhood

New roles for chromatin modifications in replication origin control

Elizabeth Suzanne Dorn 1, Jeanette Gowen Cook 1,2,✉
PMCID: PMC3230546  PMID: 21364325

Abstract

The importance of local chromatin structure in regulating replication initiation has become increasingly apparent. Most recently, histone methylation and nucleosome positioning have been added to the list of modifications demonstrated to regulate origins. In particular, the methylation states of H3K4, H3K36 and H4K20 have been associated with establishing active, repressed or poised origins depending on the timing and extent of methylation. The stability and precise positioning of nucleosomes has also been demonstrated to affect replication efficiency. Although it is not yet clear how these modifications alter the behavior of specific replication factors, ample evidence establishes their role in maintaining coordinated replication. This review will summarize recent advances in understanding these aspects of chromatin structure in DNA replication origin control.

Key words: chromatin, histone methylation, nucleosome positioning, nucleosome stability, origin, post-translational modification, replication

Introduction

Every time a cell divides, its DNA must be replicated so that a complete genome is passed on to each daughter cell. DNA replication is a highly ordered process regulated by multiple mutually reinforcing mechanisms. Because eukaryotic replication begins at hundreds to thousands of sites—termed origins—within the genome, tight regulation and coordination of the initiation, or “firing,” of these origins is needed to ensure proper duplication of the DNA.

Origins undergo three distinct regulatory phases that are coordinated with the cell cycle (Fig. 1). First, origins prepare for replication by assembling pre-replication complexes (preRC) during the G1 phase of the cell cycle. PreRCs are assembled by the binding of the origin recognition complex (ORC) to DNA and then, in conjunction with the Cdc6 and Cdt1 proteins, ORC loads the MCM helicase complex onto DNA. Once MCMs are loaded, an origin is said to be prepared, or “licensed,” for replication.1–3 At the G1-to-S phase transition, protein kinases stimulate recruitment of initiation factors, including Cdc45, the GINS complex and DNA polymerase α to individual origins to trigger MCM helicase activation and origin firing.4–8 Finally, origins that have fired are prevented from re-loading a preRC prior to the next cell division.9 This regulation is critical because inappropriate preRC assembly outside of G1 phase can result in re-replication, ultimately leading to DNA damage, cell death or genome instability.10,11

Figure 1.

Figure 1

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The regulatory phases of DNA replication that occur at origins. An origin is licensed for replication when ORC, Cdc6 and Cdt1 have loaded the MCM complex. This four member complex is the pre-replication complex (preRC). DNA replication is then initiated upon recruitment of the GINS complex, Cdc45 and DNA Polα. Finally, preRC formation is inhibited from the end of G1 until the beginning of the subsequent G1.

Although these three regulatory phases are common among all origins, not all origins are used identically. First, origins are not utilized with the same efficiency. Some initiate replication in almost every cell cycle while others rarely fire and instead are passively duplicated by a replication fork initiated at a neighboring origin.12,13 Also, not all origins fire synchronously. Some origins characteristically fire early in S phase whereas others fire late.14,15 Furthermore, it is not known how ORC selects the genomic sites that become potential origins. Budding yeast origins contain an 11 base-pair ORC-binding sequence, but there are 30 times more occurrences of this sequence in the yeast genome than in bona fide origins; thus, functional origins are not defined by an ORC-binding sequence alone.16,17 Other eukaryotic genomes in which origins have been mapped, including those of S. pombe, D. melanogaster and mammalian cells, lack a consensus ORC-binding sequence altogether despite the fact that the ORC proteins are highly conserved.18–21 These observations indicate that additional elements beyond nucleotide sequence are important for defining origin location and regulating origin function. Over the past several years, differences in local chromatin structure have been implicated in defining origins and in controlling their activity.

Chromatin is highly organized and dynamically regulated to provide access to particular regions of DNA at specific times. It is well-documented that the most efficient and early-firing origins are most often found in euchromatic regions.13,17,22 A collection of post-translational histone modifications is characteristic of euchromatin; for example, lysine acetylation is common in euchromatin. Histone lysine acetylation has been extensively linked to early origin firing, whereas decreased acetylation has been shown to delay or inhibit origin firing.23–26 Since the interaction of histone acetylation with replication initiation has been reviewed recently, acetylation will not be the emphasis of this discussion.13,27,28

Although the positive role of histone acetylation at origins has been well-documented, acetylation cannot be the only chromatin element that affects replication. Histone acetylation is enriched at promoters of active genes;29,30 however, not all promoters contain origins and not all origins are near promoters. Furthermore, if acetylation were the only chromatin element origins required, then deacetylated regions such as heterochromatin and telomeric regions would exclude origins, but functional origins have been identified in these regions.31 This review will highlight recent studies that have shed light on the role of two additional chromatin elements, histone lysine methylation and nucleosome positioning, in origin function.

Methylation

The emerging appreciation for the importance of chromatin structure in replication function prompted experiments to determine which histone modifications can be found at origins. In addition to the expected detection of histone acetylation, several methylated histone lysine residues have been found near origins. In particular, novel marks such as methylation of H3K37 and H2BK111 have been identified and correlated with origins, along with several well-studied marks such as methylation of H3K4, H3K36 and H4K20 (Fig. 2).32,33 Unlike acetylation, which is typically associated with a general opening of chromatin and active genes, methylation has been shown to both activate and repress transcription and replication.34,35 Additional complexity stems from the fact that the extent of methylation on a particular lysine can have opposite effects.36,37 Thus, diverse histone methylation events may function along with acetylation to control the precise sequence of events that are required for efficient but regulated origin firing.

Figure 2.

Figure 2

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Chart of post-translational histone modifications that show localization or regulation distinct from bulk chromatin that have been implicated in replication. The mark, its localization, timing, proposed function in regulating origin firing, and notes on correlation (or anti-correlation) are listed. The marks are arranged from top to bottom depending on whether they are proposed to inhibit origin firing, maintain a semi-accessible origin (or have an unknown function) or promote origin firing.

Histone H3K36 methylation.

Genome-wide studies of budding yeast chromatin found that trimethylation of histone H3 lysine 36 (H3K36me3) is low at early-firing origins relative to late-firing origins.35 The abundance of H3K36me3 at origins also decreases throughout S phase at the same time that monomethylation of H3K36 (H3K36me1) increases. These observations correlate H3K36 methylation with early or late replication; do individual H3K36 methylation states directly affect replication? Studies that disrupt all forms of methylation at H3K36 have suggested opposing answers to this question. For example, deletion of Set2, the H3K36 methyltransferase, suppresses the replication stress phenotype of a mutant form of FACT, a remodeling factor known to promote replication, at least at replication forks. This genetic interaction is consistent with H3K36 methylation playing a negative role in replication.38 On the other hand, H3K36 methylation was required for the accelerated S phase phenotype caused by deletion of the histone deacetylase, Rpd3.35 Deletion of Set2 also resulted in a delay in the recruitment of the replication initiation factor, Cdc45, to origins.35 Although the change was subtle, this result indicates that H3K36 methylation may play a positive role in replication. Subsequent investigation suggested a means to reconcile these seemingly conflicting conclusions.

A variety of replication parameters suggest that H3K36me1 plays a positive role in regulating replication initiation whereas H3K36me3 plays a negative role. For instance, reduction in H3K36me3 by overexpression of the human tridemethylase JMJD2A resulted in earlier replication initiation at select origins.39 Also, the recruitment of the origin initiation factor Cdc45 to yeast origins was correlated with high levels of H3K36me1 but low levels of H3K36me3.35 Additional work shed light on how H3K36me3 may mediate an inhibitory effect. Eaf3 associates with both H3K36me3 and the Rpd3S deacetylase.40 H3K36me3 is already known to be linked to Rpd3-mediated deacetylation in actively transcribed genes.40 Since histone acetylation is positively correlated with origin firing, H3K36me3 may inhibit origin firing through the Eaf3-mediated recruitment of the histone deacetylase Rpd3 and the resulting reduction in acetylation and chromatin accessibility.40 In support of this model, S phase progression was accelerated in the absence of Rpd3 or the H3 trimethyl-binders Eaf3 and Nto1.35 Furthermore, overexpression of the human H3K36me3 demethylase results in reduced H3K36me3 and increased chromatin openness.39 It still remains to be determined if all of the effects of H3K36 methylation are attributable to histone deacetylase recruitment. Interestingly, the S phase accelerating effects of Rpd3 deletion required H3K36 methylation, suggesting a role for H3K36 methylation that is independent or downstream of Rpd3. It is also not clear if all effects on S phase progression are due to events at origins or if H3K36 methylation affects replication fork progression and therefore S phase length.

The characterization of chromatin structural features specific to mono- and trimethylation and the identification of proteins able to distinguish between each mark will shed light on this issue. Additionally, it is not yet clear how mono- versus trimethylation is controlled at different origins. While the effects of each methylation state could be distinct, a single methyltransferase is responsible for all levels of methylation. How can a single enzyme place a different number of methyl groups at distinct locations or in different situations? In the case of the human methyltransferase MLL1, an inhibitory tyrosine in the active site of MLL1 prevents di- or trimethylation in the absence of binding partners that are thought to induce a conformational change in MLL1.41 Perhaps a similar scenario is utilized to control Set2-dependent di- and trimethylation. An important direction of future work will be focused on the elucidation of the mechanisms and signals that differentiate the levels of histone methylation.

Histone H4K20 methylation.

Studies of cell cycle-dependent changes in global histone modifications in human cells showed that histone H4K20me1 is high in late mitosis and throughout G1 but low in S phase.42 Depletion of Set8 (PR-Set7), the enzyme responsible for H4K20me1 in humans, causes replication stress and cell cycle arrest suggesting that H4K20me1 may be important for replication.43,44 Experimental manipulations leading to aberrant persistence of Set8, and therefore H4K20me1 during S phase resulted in extensive genome re-replication, a phenomenon characterized by re-firing of origins within a single cell cycle.45,46 Furthermore, H4K20me1 can be detected at each of a select group of tested human origins.47

Tethering Set8 to an artificial locus by expression of a Gal4 fusion protein not only induced ectopic H4K20me1, but also promoted preRC formation at that site, indicating a positive role for H4K20me1 in defining origin location or promoting preRC assembly.47 It is not yet clear how H4K20me1 promotes origin licensing but H4K20 methylation has been detected in conjunction with acetylation on lysines 5, 8 and 12 of histone H4, which themselves are thought to promote preRC assembly by facilitating DNA accessibility. One model for the role of H4K20me1 proposes that a burst of H4K20me1 in mitosis leads to an increase of H4 acetylation in G1 that then facilitates preRC formation.47

As with H3K36 methylation, the mechanism by which H4K20me1 affects recruitment of replication proteins to origins is still unknown. H4K20me1 may promote a particular chromatin structure at origins that is compatible with replication factor recruitment. It is also possible that the different methylation states, either alone or in combination with other marks, are recognized specifically by a replication protein through a mechanism similar to that used by 53BP1, which binds to H4K20me2 as part of the checkpoint response.48 Alternatively, these marks may function in a signaling cascade leading to other histone modifications, such as lysine acetylation, that ultimately promote origin licensing.

In contrast to the suggested stimulatory role of H4K20me1, H4K20me2 may function to inhibit re-licensing of origins in S phase. Unlike H4K20me1, which declines in S phase, H4K20me2 (catalyzed in humans by the Suv4-20h1 and Suv4-20h2 enzymes) increases during S phase, potentially replacing the permissive monomethylation mark with dimethylation.48 Interestingly, the simultaneous presence of H4K20me2 and H4K16ac at early replicating domains in S phase persisted until it was removed in the following G1 when preRC formation occurs.49,50 This dual mark on the same histone H4 molecule was also detected in D. melanogaster, where H4K16ac was enriched at origins containing H4K20me2.25,51–53 This association could implicate H4K20me2 (like H4K16ac) in maintaining an open, but also inactive or poised, chromatin state with respect to origin licensing. The presence of H4K20me2 in cells undergoing a normal S phase (i.e., without re-replication) indicates that H4K20me2 may inhibit re-licensing of origins during S phase either directly or by replacing the monomethylation mark. Additionally, the association with H4K16ac suggests that H4K20me2 (and possibly H4K20me3) may prevent re-licensing of origins in S phase without limiting origin accessibility for replication in subsequent cell cycles. While deletion of Suv4-20h has been shown to have major consequences for proliferation in both mice and Drosophila (reviewed in ref. 48), assays specifically monitoring replication are needed to determine if H4K20me2 or H4K20me3, like H4K20me1, directly impact origin function.

Histone H3K4 methylation.

Histone modification localization data gathered by the ENCODE consortium have identified a correlation between high levels of H3K4 trimethylation (H3K4me3) and early replicating regions in human cells.54,55 In particular, regions shown to replicate early in the cell cycle were enriched for H3K4me2/3 specifically while late-replicating sites were depleted of H3K4me2/3.56 While these correlations may be partially influenced by gene density given the resolution of the ENCODE projects, evidence from other organisms also supports a role for H3K4me at origins. For instance, H3K4me3 has been correlated with distinct sets of ORC-binding sites in D. melanogaster.57 The H3K4me3 mark was originally identified at the 5′ ends of actively transcribed genes and has thus been intensively studied for its role in gene expression.58,59 Less is known about the dynamics of H3K4 methylation specifically at origins, however, and it remains to be determined if these marks play direct roles in origin activity.

The enrichment of H3K4me3 near early-firing origins compared to late-firing origins suggests a positive role in regulating firing rather than origin licensing, since both early and late-firing origins are licensed together in G1. ChIP studies of budding yeast examined the location of H3K4me3 genome-wide in synchronized cells. As cells progressed through S phase, H3K4me3 was lost at early-firing origins before late-firing ones.60 ChIP analysis at a subset of a few defined human and monkey origins in synchronized cells found a similar enrichment of H3K4me3 at known early-firing origins compared to late-firing origins.61 Interestingly, both studies also demonstrated transient increases in H3K4me3 during origin firing. This H3K4me3 spike occurred at origins specifically, not generally across all chromosomal locations.61 Correlation between H3K4me3 localization to origins and replication initiation has clearly been established; nevertheless, it is still unclear whether H3K4me3 regulates replication or if replication regulates the placement of H3K4me3. Technical hurdles currently make it difficult to precisely determine if the changes in H3K4 methylation precede or follow origin firing.

The accumulation of H3K4me3 at origins after DNA damage could indicate an additional negative role for H3K4me3 in regulating replication during a checkpoint response. In human cells, DNA damage resulted in phosphorylation of the human H3K4 methyltransferase, MLL, by the checkpoint kinase ATR and simultaneous accumulation of H3K4me3 at late origins. As a consequence, DNA replication was blocked because Cdc45 loading was inhibited.62 In the case of DNA damage, late origins are blocked from firing by the S phase checkpoint, but firing resumes after repair is complete. It is possible that induction of H3K4me3 at origins in cells with damaged DNA limits origin firing by repelling Cdc45, and indeed, Cdc45 binding to H3 in vitro was reduced when H3K4 was trimethylated.62 H3K4me3 correlates positively with origin firing in unperturbed S phases, but it accumulates at blocked origins after DNA damage. These observations could indicate that H3K4me3 is needed in the origin firing process prior to Cdc45 loading, but that its persistence at an origin actually blocks progression to Cdc45 loading. It is also possible that accumulation of H3K4me3 at origins during a DNA damage response is required to maintain origin chromatin in a state that is semi-accessible for DNA repair or origin firing during recovery.

How would H3K4me3 maintain this putative semi-accessible state? One can extrapolate a potential mechanism for H3K4 methylation in replication from its role in transcriptional regulation. In both human cells and D. melanogaster, the PHD finger of the NURF complex has been shown to link H3K4me3 with chromatin remodeling at promoters to tune Hox gene expression during development.63 H3K4me3 could be similarly important in recruiting remodelers to maintain open chromatin near origins. Alternatively, or in conjunction with remodeling, H3K4me3 may mediate open chromatin through stimulating H3K9/14 acetylation. H3K9/14ac is known to open chromatin and has been found in conjunction with H3K4me3 at human origins.61 Initially, assembly of early replication factors onto DNA may depend on an H3K4me3-induced open chromatin state, but then H3K4me3 may need to be removed to accommodate recruitment of the Cdc45 initiation factor to trigger origin firing.43

Nucleosome Structure

Like post-translational histone modifications, the emerging role of nucleosome architecture in regulating origins has also led to studies examining the composition of origin-associated nucleosomes and their positions relative to origins. Similar to transcriptional start sites, origins tend to be nucleosome-free regions,64,65 and recent studies have provided insight into the relationship between nucleosome position and origin function. The catalytic “writers” and “erasers” of the histone code are thought of as the principal means to regulate histone modifications. However, nucleosomes are not static and are subject to highly dynamic subunit exchange and remodeling. In fact, Drosophila ORC-binding sites are correlated with high levels of H3.3, a marker of dynamic and active chromatin.66,67 Thus, it is possible that changes in chromatin status are not just the result of enzyme activity, but are also brought about by exchange of histones themselves.

Nucleosome composition and stability.

The status of the somatic linker histone H1 has been correlated with replication regulation. Studies utilizing X. laevis extracts demonstrated that the presence of unphosphorylated H1 inhibited replication.68,69 The presence of a linker histone has also been associated specifically with late origin firing in P. polycephalum, further supporting its inhibitory role. Likewise, upon knockdown of the linker, synchronized cells showed an overall increased rate of replication, again indicating that the histone H1 normally limits replication. Manipulations to induce histone H1 phosphorylation stimulated late origins to fire earlier, suggesting a mechanism to relieve replication inhibition by H1.70 In mammalian cells, phosphorylated H1 accumulates throughout S phase, is added to late-replicating regions de novo at the time of replication, and is maintained until the end of mitosis.71 These results suggest that replication is positively linked to phosphorylated linker histones and negatively linked to unphosphorylated H1. While the presence of phosphorylated H1 has been shown to decrease the stability of the nucleosome-DNA interaction,72 it is unclear if linker histones are actually regulating initiation or another aspect of replication. Experiments in mammalian cells have provided evidence for a mechanism in which Cdc45 association with replication foci facilitates replication by inducing Cdk2-mediated phosphorylation of H1 and decondensation of DNA.71 These data cannot differentiate whether this decondensation, or opening of chromatin, is critical for initiation of late-firing origins (which are often found in condensed regions) or if it is required for other aspects of replication such as fork progression.

Nucleosome positioning.

Nucleosome mapping studies in both yeast and human cells have shown that early replicating regions are most frequently located in open, nucleosome-free regions.64 In budding and fission yeast, highly efficient origins are correlated with sites of nucleosome depletion. Firing efficiency was severely reduced in fission yeast when nucleosomes were allowed to encroach upon an origin by deletion of a nucleosome-disfavoring element, polyA(20).64,73 A system that shifted nucleosomes even further away from origins demonstrated, however, that initiation of replication requires nearby nucleosomes as well.74 These observations suggest that nucleosomes must be exactly positioned for accurate origin activity. Corroborating this model, disruption of proper regulation of the histone remodeler FACT limited the effectiveness of MCM loading (preRC assembly) at early origins.75 Thus, it is clear that nucleosomes must be precisely positioned near, but not on, origins. What determines where nucleosomes are positioned?

Utilizing high throughput ChIP-seq, Eaton et al. identified 238 sequences in the budding yeast genome that ORC does not bind to, despite bearing sequences predicted to be highly compatible with ORC binding and therefore, origin function.76 Nucleosome positioning at these non-origin sites differed from that of functional (ORC-binding) origins. Both classes of sequences intrinsically repel nucleosomes; however, the ORC-binding site of the functional sequences is located asymmetrically in the nucleosome-free region and, further, nucleosomes are positioned with a high degree of periodicity. Also, the bona fide ORC-binding sequences include the ORC-binding site followed by an A-rich element, but the non-origin sites do not. Interestingly, the nucleosome-free region is 90 base-pairs larger than the ORC footprint. The additional sequence elements may maintain a larger open region to accommodate MCM loading.76 Together, these studies indicate a role for DNA sequence in positioning the nucleosomes near origins. Even human replication initiation zones, which lack a consensus ORC-binding sequence, are AT-rich, suggesting that sequence may also function in positioning nucleosomes at human origins.

Nevertheless, strict nucleosome positioning and phasing, which are characteristics of the most highly efficient origins in yeast, cannot be explained by sequence elements alone. Not only do higher eukaryotes such as human cells lack canonical origin-identifying sequences, but even budding yeast requires additional factors such as ORC to maintain proper nucleosome localization. In the absence of ORC, nucleosomes shifted inward toward the ORC binding sequence—but did not cover it—and the periodicity of nucleosomes near origins was reduced.77 ChIP studies in budding yeast indicated that, in addition to DNA interactions, ORC interacts with nucleosomes through the N-terminal BAH domain of the Orc1 subunit of ORC for positioning nucleosomes and stable association with chromatin at select origins. Thus, both ORC-DNA and ORC-chromatin interactions may contribute to determining nucleosome positioning and where ORC will stably bind to establish origin location.78

Because the DNA sequence plays a limited role in defining ORC binding in higher eukaryotes, the identity of origins (ORC-binding sites) likely depends more heavily on nucleosome interactions with replication proteins. The BAH domain in Orc1 is conserved in many organisms including human Orc1.79 It will be interesting to determine whether other replication proteins (such as Cdc45) also contain nucleosome-interacting domains that regulate the interaction between the replication machinery and chromatin and at the same time help position the nucleosomes to direct the formation of proper origin structure. One hurdle for such studies is to dissect any potential origin function for a histone modifying enzyme or nucleosome remodeler from other roles in DNA metabolism such as replication fork progression, gene expression, DNA repair, etc. FACT, for example, is implicated in efficient initiation by contributing to MCM loading at origins, and it is also needed for unimpeded replication fork progression.75,80 Artificial tethering assays in which a chromatin modifying enzyme fusion is forcibly localized to an origin have been helpful in showing that a given enzyme can influence an engineered origin, but demonstrating distinct roles in native chromatin beyond simply localizing the enzymes or their marks to origins remains an ongoing challenge for the field.

Concluding Remarks

It is important to understand how proper replication and proliferation is achieved because aberrant proliferation can lead to a variety of disease states. Perturbed origin regulation can lead to premature cellular aging,81 affect tissue regeneration after heart attacks,82 and may play a role in oncogenic transformation.83–85 The addition of nucleosome positioning and histone methylation to the growing list of origin-associated chromatin modifications further reinforces the idea that chromatin structure at origins is a critical aspect of the replication program.

By what mechanism do these changes in chromatin alter initiation? One possibility is that the chromatin at an origin may be “read” by effector proteins that either bind to replication factors, or are replication factors themselves, and that this binding directly changes the localization and activity of the replication machinery at origins. Protein domains known to bind acetylated or methylated histones, such as bromo- or chromo-domains (among others) have not been identified in replication factors thus far. This absence could either indicate that the relevant readers of methylated nucleosomes at origins are bridging proteins that link chromatin to the replication machinery, or that there are new binding motifs that have yet to be identified.

In addition, individual alterations in chromatin structure may function as part of a signaling cascade with the ultimate goal of modulating acetylation to facilitate the loading of replication factors. One example is the recruitment of a histone deacetylase by H3K36me3. Altogether, a collection of dynamic histone post-translational modifications may work together with the shared aim of regulating histone acetylation and thus, the relative accessibility of origins. Furthermore, marks such as histone methylation have also been implicated in the recruitment of chromatin remodelers, some of which are important for unperturbed replication. Future studies will be crucial to differentiate between the various models and to elucidate the cellular signals that bring about changes in chromatin structure relevant to origin regulation.

Acknowledgements

The authors are grateful to B. Strahl, D. MacAlpine and members of the Cook lab for helpful comments on the manuscript. E.S.D. and J.G.C. are supported by NIH R01GM083024 and AHA 0865097E.

Abbreviations

preRC

pre-replication complex

ORC

origin recognition complex

MCM

minichromosome maintenance complex

GINS

go, ichi, ni and san complex

FACT

facilitates chromatin transcription complex

MLL1

mixed-lineage leukemia complex

ChIP

chromatin immunoprecipitation

ENCODE

encyclopedia of DNA elements

PHD

plant homeo domain

NURF

nucleosome remodeling factor

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