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. 2011 Jan 1;6(1):13–19. doi: 10.4161/epi.6.1.13331

Chromatin landscape

Methylation beyond transcription

Joshua C Black 1, Johnathan R Whetstine 1,✉
PMCID: PMC3052912  PMID: 20855937

Abstract

The nucleus is organized and compartmentalized into a highly ordered structure that contains DNA, RNA, chromosomal and histone proteins. The dynamics associated with these various components are responsible for making sure that the DNA is properly duplicated, genes are properly transcribed and the genome is stabilized. It is no surprise that alterations in these various components are directly associated with pathologies like cancer. This Point-of-View focuses on the role the chromatin modification landscape, especially histone 3 lysine 9 methylation (H3K9me) and heterochromatin proteins (HP1) play in regulating DNA-templated processes, with a particular focus on their role at non-genic regions and effects on chromatin structure. These observations will be further extended to the role that alterations in chromatin landscape will contribute to diseases. This Point-of-View emphasizes that alterations in histone modification landscapes are not only relevant to transcription but have broad range implications in chromatin structure, nuclear architecture, cell cycle, genome stability and disease progression.

Key words: chromatin, heterochromatin, euchromatin, lysine methylation, KMT, KDM, histone methyltransferase, histone demethylase, HP1, lamin, histone demethylases, histone, H3K9, H3K9me3

Chromatin and Nuclear Architecture

The eukaryotic genome is packaged into chromatin. Chromatin is a highly ordered structure that contains DNA, RNA, histones and other chromosomal proteins. Chromatin was originally classified into two domains, euchromatin and heterochromatin, based on the density of staining of the nucleic acid in micrographs.1 The definition of these domains has since been expanded. Euchromatin is gene-rich, transcriptionally active, hyperacetylated, hypomethylated chromatin. Conversely, heterochromatin is transcriptionally inactive, gene-poor, hypoacetylated and hypermethylated.1,2 These domains are intricately organized in the nucleus with heterochromatin predominantly localized to the nuclear periphery and euchromatin at the interior of the nucleus. This architecture is maintained by dynamic associations with the nuclear lamina. The nuclear lamina is primarily composed of an intricate matrix of 4 lamin proteins Lamins A, B1, B2 and C.3 The lamins interact with chromatin and each other to create a specific three-dimensional nuclear architecture. Disruptions in lamins lead to deformed nuclei, genome instability, age-related diseases and cancer.4

The basic unit of chromatin, the nucleosome, is composed of two copies of the histones H2A, H2B, H3 and H4 wrapped with 146 bp of DNA.5 In chromatin's simplest form, the repeating nucleosomal units adopt a decondensed beads-on-a-string configuration. Internucleosomal, intrafiber and interfiber interactions result in the progressive condensation of chromatin.5 The ability of chromatin to condense can be regulated in part by post-translational modification (PTM) of the N-terminal tails of the histones including acetylation, phosphorylation, ubiquitination and methylation.2 Modification of the tails can influence both internucleosomal and chromatin fiber interactions to help condense or open local chromatin domains.1 Histone PTMs also serve as docking sites for chromatin associated proteins and chromatin remodeling complexes.1,2 Thus the chromatin structure is characterized by the degree of chromatin condensation, the location within the nuclear architecture and the types of histone modifications.

Site, Degree and Placement Matter

The majority of research regarding histone modifications has centered on their role in transcription. Numerous genome-wide studies demonstrate that the distribution of methylated lysines within the histones and the degree of methylation have a specific, unique placement with respect to open reading frames (ORFs).6–8 These studies have highlighted the unique nature of histone modifications and allowed correlative relationships between placement and outcome to start to emerge. For example, H3K4me3 is found at transcription start sites and strongly correlates with active gene expression, while H3K36me3 is found in the body of actively transcribed genes.6,7 In contrast, H3K9me3 correlates with repressed genes when found at the promoter.6,7 However, H3K9me3 enrichment within the body of a gene correlates with gene expression.7,9,10 These few examples underscore the specificity and defined placement of individual marks (Fig 1).

Figure 1.

Figure 1

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Enzymes controlling histone methylation dynamics and chromosomal domains of histone methylation. Lysines are mono-, di- and trimethylated by multiple histone methyltransferases (KMT). The different KMT are shown in the left-most part. The histone lysine demethylases (KDM) remove methyl groups from the lysines. The different KDMs that have been discovered are in the left part adjacent to the reactions. The sites the KMTs and KDMs modify are indicated next to their names. The degree of methylation these enzymes impact is based on their clustering (see color box code: blue, methylate from unmodified to trimethylated; green, unmodified to dimethylated; brown, monomethylation to trimethylation; black, only function at the indicated modification sate). The methyltransferases with an * indicate the last reaction is not as strong. The right part summarizes localization data indicating the relationship of each modification to active open reading frames, as well as particular chromosomal domains. For open reading frames: ORF, open reading frame; TSS, transcriptional start site; UTR, untranslated region; NC, no correlation to open reading frame; NA, not on active genes and ND, not determined. For chromosomal domains: T, telomere; ST, subtelomere; C, centromere; PC, perictromeric; GD, gene deserts; RD, repetitive regions and LAD, lamin associated domains. Data on chromosomal domains of modifications was compiled from references 6, 7, 14 and 59. We apologize to all those whose work is summarized in this figure that we were unable to cite due to space limitations.

The complexity of methylation is further exemplified by diverse enzymes evolved to regulate methylation and demethylation (Fig. 1). Each site and degree of modification is regulated by distinct enzyme families. For example, the KDM4/JMJD2 family has been shown to demethylate H3K9me3, H3K36me3 and H1.4K26me3.11–13 Since both H3K9/36me3 are found in the coding region of genes, both repress gene expression when targeted to promoters and have an enzyme family responsible for their demethylation, we hypothesize that these modifications may have a similar role or a coordinate function in certain places in the genome, which needs further investigation. These few examples emphasize the importance of regulating the modification state (e.g., tri-methylated versus mono-methylated) and placement providing another mechanism by which pathologies might occur or be potentiated (see below).

Certain modification states are associated with transcription, but this is not the only role chromatin modifications play in vivo (Fig. 1). We would speculate that certain histone modification patterns (i.e., H3K9me3) have such a dramatic impact on the organism because of structural changes that impact other DNA-templated processes. There is a strong possibility that the modification changes are coupled to more than one process, which is the case for transcription and DNA replication. Recent genome-wide observations also suggest that the chromatin state has an independent role in DNA replication (see below). Therefore, a distinct need exists to better understand how histone modifications are controlled under more dynamic events such as cell cycle progression. It is important to consider the roles histone modifications and their associated modifiers have outside of transcription. We will highlight some of these relationships below.

Shaping the Chromatin Landscape through Histone 3 Lysine 9 Methylation

The relationship between the chromatin landscape and transcription has demonstrated that different histone modifications have distinct placement throughout the body of a gene. However, it is becoming apparent that these paradigms extend beyond transcription and will define chromatin structure and nuclear architecture. Substantial data exists on numerous histone modifications, however, for the purpose of this review we will focus on the distribution and role of H3K9 methylation.

H3K9me1.

H3K9me1 is generated by specific methyltransferases (e.g., KMT1C/G9a) or demethylases (e.g., KDM3A/JMJD1A or KDM4D/JMJD2D).11 H3K9 monomethylation is enriched in the promoter and 5′ UTR with decreasing levels in coding regions of active genes and minimal enrichment in non-genic regions.6,14 This sharply contrasts with H3K9me3, which is found in non-genic regions, repressed promoters and coding regions of some active genes.6,7,10,14 H3K9me1 could act as a buffer between activation and repression by allowing rapid methylation and demethylation. However, the exact role H3K9me1 performs is not known.

H3K9me2.

H3K9me2 is primarily generated through methylation by the KMT1/Suv39 methyltransferase family and the KDM4/JMJD2 demethylase family (Fig. 1).11 H3K9me2 demarcates heterochromatin, particularly non-genic regions. H3K9me2 is prevalent in gene deserts, pericentromeric and subtelomeric regions, with little being observed at individual active or silent genes (Fig. 1).14 The H3K9me2 distribution occurs in large tracts several megabases in size encompassing both non-coding and gene containing DNA. These large organized chromatin K9-modifications (LOCKs) were conserved between mouse and human and could arise and expand during differentiation.15 Wen and colleagues hypothesize that these stretches lock-down regions of the genome that would become unneeded after differentiation. If this is true, H3K9me2 would play a role in structure and consequently silence genes within this region. LOCK domains are also aberrantly regulated in cancer possibly accounting for changes in gene expression, chromosome structure and nuclear architecture.15

H3K9me2 domains are also strongly correlated with binding of Lamin B1. Mapping of Lamin B1 interacting domains demonstrated that inactive genes are preferentially located at the nuclear periphery in association with the nuclear lamina.16 The genomic blocks associated with the lamina change during differentiation, underscoring the dynamics of the interaction. The Lamin B1 associated regions are depleted of H3K4me3 and RNA polymerase II and enriched for H3K9me2.16 Taken together, these data suggest that H3K9me2 domains are critical determinants of higher order chromosome structure and nuclear architecture.

H3K9me3.

KMT1A,B/SUV39H1/2 are the primary methyltransferases responsible for H3K9me3 (Fig. 1).11 H3K9me3 has been thought to occur at heterochromatin regions and at repressed promoters. However, studies interrogating specific genes or looking at the entire genome have clearly demonstrated that this methylation site and state are associated with coding regions as well.7,9,10 The exact role this modification has on coding regions is not known, but emphasizes the need to better understand the importance of placement. These observations suggest that H3K9me3 may have a role in both euchromatin and heterochromatin.

Recent ChIP-Sequencing analyses have demonstrated that H3K9me3 is prevalent at many non-genic regions including the repetitive satellite DNA, centromeric and pericentromeric DNA and long terminal repeats of transposons.7,14,17,18 Interestingly, H3K9me3 is depleted at telomeres, but not sub-telomeric regions, suggesting that telomeres and subtelomeric regions are structurally distinct and different from other non-genic regions.

Like H3K9me2, H3K9me3 also exists in large blocks comingled with H4K20me3, especially in pericentromeric chromatin.7,14,17,18 These large tracks do not strongly overlap with either H3K9me1/2, distinguishing LOCKs and large H3K9me3 tracks. It remains unclear how these large chromatin domains are initiated and maintained. One might speculate that the combined localization and activity of KMTs and KDMs are responsible for establishing, maintaining and restricting these domains. These large H3K9me3 blocks could be important in cellular senescence as H3K9me3 is critical for formation of senescence associated heterochromatin foci (SAHF).19 SAHF form as mammalian cells age and irreversibly exit the cell cycle. Specific genomic regions condense into compact, densely DAPI staining, H3K9me3 containing foci. Formation of these foci is critical for senescence and is dependedent on KMT1A/1B.20 It is unclear if these foci are formed from large blocks of H3K9me3, but this presents an attractive model for demarcating and coordinating repression and aggregation of genomic regions in SAHF.

We have concentrated on the positioning and structural roles of H3K9 methylation. However, many of the insights and observations hold for additional methyl modifications. For instance, H4K20me3 is enriched specifically at pericentromeric chromatin, but not gene deserts and subtelomeric loci.14 H3K27me3 enrichment peaked at silent genes and subtelomeric chromatin, whereas H3K27me1 is enriched at active genes.14 Both modifications occur less frequently at other non-genic regions.14,17 Like H3K9me2/3, H3K27 can also be found in expansive domains.17 Taken together, these few examples demonstrate that both genic and non-genic regions have unique combinations of histone modifications that may allow diverse structural features to be created and modified to distinguish subtypes of heterochromatin.

Heterochromatin Proteins: Similar Proteins, but Diverse Functions

A key interpreter of H3K9 methylation is the heterochromatin protein 1 (HP1) family of proteins. HP1 proteins are conserved from yeast (Swi6 and Chp2) to mammals (HP1α, HP1β and HP1γ).21 HP1 proteins bind methylated H3K9 and H1.4K26 through their conserved chromodomain with highest affinity for the tri-methylated state. Even though the chromodomains are highly conserved between isoforms, HP1α, HP1β and HP1γ have diverse and distinct functions. In the context of euchromatin, HP1α, HP1β are recruited to repressed gene promoters, while HP1γ associates with the coding regions of active genes.10 Re-localization of HP1β helps establish a repair-competent chromatin environment following DNA damage.22 Consistent with distinct functions, immunofluorescent analysis of human and murine cells, Drosophila polytene chromosomes and C. elegans embryos has demonstrated that HP1 isoforms occupy distinct chromosomal domains and compartments.23–27 This suggests a model whereby distinct HP1 proteins define different chromatin structural regions and are important for regulating DNA-dependent processes in these domains. In agreement with his notion, Swi6 and HP1α are critical regulators of DNA replication of pericentric heterochromatin.28–31 In addition, HP1 proteins are likely important contributors to nuclear architecture. HP1α and HP1β co-immunoprecipitate with the Lamin B Receptor, an integral component of the nuclear lamina. Disruption of this interaction results in disorganization of the nuclear lamina.32

In mammalian cells, HP1α, HP1β and H3K9me3 are important for condensing pericentric regions to maintain transcriptional repression and to prevent these regions from being aberrantly replicated.31 Mammalian HP1α and HP1γ also directly interact with components of the replication fork, including CAF-1. The HP1α and CAF-1 association is critical for maintaining the late replication of pericentric heterochromatin during S phase.31 We would speculate that the distribution of H3K9me3 and HP1 proteins (not just restricted to HP1α) will have a comparable impact on other regions of the genome. However, the best way to resolve this relationship will require more genome-wide analysis of H3K9me domains, HP1 proteins and distribution of DNA replication. These studies will start to uncover whether methylation domains might be important for replication as well as transcription. Indeed, in Drosophila Kc cells, HP1a is critical for replication timing of centromeric repeats, as well as allowing early replication of euchromatic regions.33 Consistent with this idea, a number of studies have implicated chromatin accessibility as a major factor in DNA replication.34–36

Chromatin Landscape: Impacting Cell Cycle Directly and Indirectly

During the course of cell cycle chromatin undergoes dynamic cycles of compaction and decompaction in order to duplicate and pass on the genome. Early studies of replication timing clearly demonstrated that distinct chromatin domains replicated at different times during S phase.37,38 Heterochromatin regions associated with the nuclear lamina replicate later, while euchromatic regions were predominantly early replicating and in the interior of the nucleus. Changes in the chromatin microenvironment could dictate cell cycle and proliferation rates both directly (cell cycle gene regulation) and indirectly (alterations to replication timing). For example, KMT4/Dot1 is required for efficient entry into S phase, which is the result of direct transcriptional control of cell cycle genes through H3K79 dimethylation.39 Similarly, KMT6/EZH2 regulates H3K27me3 levels at transcriptional targets involved in cell cycle—Cyclin D1, E1 and A2.40 These results emphasize that methylation of cell cycle genes can be a key determinant in cell cycle.

Changes to the chromatin architecture also influence cell cycle, especially the initiation and elongation of DNA replication. Genome-wide and locus-specific analyses have demonstrated that chromatin accessibility is a critical determinant of DNA replication timing.34–36,41 Active gene expression and DNase I hypersensitivity are associated with earlier DNA replication, while heterochromatin and H3K9me3-enriched regions tend to replicate later (e.g., satellites).42 Laboratories looking at specific loci or evaluating replication on a genome-wide level have clearly demonstrated that transcription is not required for early replication. For example, increasing or decreasing histone acetylation at a targeted locus can result in earlier or later replication, without altering transcription.43,44 These observations strongly suggest that an open chromatin configuration is a strong indicator of whether a region will replicate in early or late S phase. These data suggest that chromatin architecture is dynamically changing during S phase and is required to ensure proper replication timing.

Consistent with this idea, regions with high nucleosome turnover rates have increased enrichment of Orc2.45 High nucleosome turnover rates provide another possible function for large tracts of histone modifications. These large tracts could ensure that certain regions maintain a specific chromatin fate by perpetually maintaining enough modified histones to prevent loss by high rates of nucleosome turnover. This mechanism would also protect non-dividing cells from modification loss due to histone turnover. Furthermore, the specified chromatin architecture is adaptable to change during development and differentiation. For example, transcriptionally repressed regions that become active after differentiation replicate earlier; however, induced pluripotent stem cells have a replication timing pattern that is more similar to ES cells, not the original differentiated cell-type they were derived from.46 Understanding how histone modifications, chromatin regulators and chromatin binding proteins dictate this cellular memory and result in re-establishment of replication timing will be key to understanding how the genome is organized and stabilized over generations.

From Landscape to Disease

Cancer.

A number of laboratories have demonstrated that methylation balance is required for normal development and cancer evasion.47,48 Methyl deficient diets result in increased incidence of liver cancer.49 Consistently, aberrant regulation of H3K9me3, H3K27me3 and H4K20me3 results in genome instability and tumorigenesis. KMT1A/B knockout mice have increased genomic instability, aberrant telomeres and high rates of lymphoma.50 The imbalance in H3K9me3 is likely very important for tumorigenesis because in medulloblastomas, H3K9me3 methyltransferases are deleted, while demethylases are amplified.51 In human prostate cancer cells, loss of KMT1A and KMT6A/EZH2 results in chromosome gain, abnormal centrosome morphology and G2/M arrest without substantial changes in gene expression.52

The importance for KMT and KDM balance in cancer also extends to other histone modifications. For example, ectopic expression of the H3K27me3 methyl-transferase KMT6A induces invasion and colony formation, while loss of EZH2 inhibits proliferation, tumor growth and metastasis.53,54 The loss of the H3K27me3 demethylase KDM6A/UTX results in increased cell proliferation and correlates with poor outcome in multiple cancers.55 To date, KDM6A is the only demethylase observed with inactivating point mutations associated with malignancy.55 While these studies clearly highlight the importance of regulating methylation, it is unclear whether the changes caused upon mis-regulation of these enzymes are direct changes in gene expression or alterations in chromatin structure and nuclear architecture. We would hypothesize that both are involved and that changes in non-genic regions and chromatin structure are key determinants of cancer pathologies. Consistent with this notion, cancer cell lines, as well as those having undergone induced transformation, have altered nuclear morphology.56 Perhaps these changes are associated with nuclear lamina and associated chromatin domains. Interestingly, elevated Lamin A levels increase invasion, migration and correlate with poor clinical outcome in colorectal cancer.57

Premature aging.

Mutations in Lamin A also lead to Hutchinson Gilford Progeria syndrome (HGPS), a disease of premature aging. Expression of mutant Lamin A leads to abnormal nuclear morphology, loss of H3K9me3, H3K27me3, delocalization of HP1α and HP1β and dissociation of heterochromatin from the nuclear periphery.4 These results emphasize the importance of maintaining nuclear structure integrity and the importance of the lamina in maintaining the chromatin environment so that aging-related pathologies are avoided.

Future Directions

With the increasing availability of genome sequencing data it will be imperative to examine the relationships between histone modifications, modifying and remodeling complexes, heterochromatin proteins and transcription outside of annotated gene regions. We must also be cognizant that large scale genomic studies are merely snapshots of a population of events, but the processes being regulated are extremely dynamic. It will be important to consider how histone modifications and heterochromatin proteins are re-distributed during DNA replication, mitosis and differentiation.

We should also consider that the modifications themselves are not as important as the resulting chromatin structure they establish. We must develop new techniques to accurately measure chromatin compaction, chromosome associations and chromatin structure in cells. The emergence of chromosome conformation capture (3C) technology and its evolved variants will help to define chromosome domains and regions responsible for associations. Recent work combining 3C with high throughput sequencing capabilities (HI-C) demonstrates that chromosomes can be subdivided into at least two domains that correspond with typical chromatin modification patterns.58 By comparing these types of analyses at high resolution with histone modifications, HP1s and lamin associated regions, one may be able to better understand how these domains influence chromatin fiber association with the nuclear matrix and how these associations change during development and differentiation.

Abbreviations

HP1

heterochromatin protein 1

H3K9me3

histone 3 lysine 9 trimethylation (or other modifications)

PTM

posttranslational modification

ORF

open reading frame

UTR

untranslated region

LOCKs

large organized chromatin K9-modifications

SAHF

senescence associated heterochromatin foci

3C

chromosome conformation capture

HI-C

high through put chromatin capture

CAF-1

chromatin assembly factor 1

HGPS

Hutchinson Gilford Progeria syndrome

Footnotes

References

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