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Sangamo BioSciences, Inc., Richmond, CA 94804
2To whom correspondence should be addressed. E-mail: furnov{at}sangamo.com.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONDISCUSSIONLITERATURE CITED |
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KEY WORDS: • methylation • chromatin • transcription • histone deacetylase • histone acetyltransferase • methyltransferase
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONDISCUSSIONLITERATURE CITED |
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): 1) signal transduction pathways that are based on "bucket brigade" cascades of enzymes—typically, kinases—that impart slight and transient covalent modifications, such as a phosphate, on target molecules; 2) genomic signaling pathways involving macromolecules such as transcription factors that control mRNA production levels and are themselves frequently also under control by signal transduction cascades involving phosphorylation or allosteric regulators—for example, estrogen or thyroid hormone.
Regulatory pathways in eukaryotic genomes are now known to extensively exploit covalent modification of its components by physically slight chemical moieties such as the methyl, acetyl and phosphate groups (2
,3
). A surprising and important development of the past 3 y has been the realization of a much greater than previously thought role of protein methylation in genome control pathways (4
), which can now be added to the methylation of DNA (5
) as a major phenomenon in nuclear biology.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONDISCUSSIONLITERATURE CITED |
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Genomes of mammals carry a considerable amount of repetitive DNA (at least 50% of total content (6
). Far from an innocuous passenger, much of this burden is, in fact, derived from genomic parasites that are capable—under certain circumstances—of propagating further and expanding to overwhelm the host genome (7
). The genome’s defense pathway (8
) is to impose a state of transcriptional silence on these elements [silencing of repetitive DNA is a phenomenon found in many other eukaryotic taxa, for example, fungi and plants (9
)]. The severity of the threat posed by genomic parasites necessitated the evolution of a very robust and stable mode of repression—in mammals, the solution that evolved involves a functional connection between DNA methylation and transcriptional repression (10
).
The bulk of methylation in mammalian DNA occurs on position 5 of the pyrimidine ring of cytosine within the context of the dinucleotide cytosine guanine [CG3
; historically referred to as cytosine guanine dinucleotide (CpG)]. In selecting for this specific modification, evolution took an interesting route: cytosine is prone to deamination that yields uracil—a base not commonly found in DNA and efficiently removed by the mismatch repair machinery. In contrast, deamination of 5-methylcytosine yields thymine—not only does this reaction occur more efficiently than the deamination of cytosine to uracil, but it also yields a mismatch (guanine/thymine, G/T) that is repaired much less efficiently. Thus, 5-methylcytosine is mutagenic and, consequently, the dinucleotide CpG occurs at considerably lower frequency in mammalian genomes than would be expected from simple combinatorial calculations based on GC content and is typically found within GC-rich areas termed "CpG islands" (5
). In normal human cells, most of the nonpromoter CpG islands, including those found in repetitive DNA, are hypermethylated, whereas those found in promoters of active genes are demethylated. Tumor cells have a deregulated genome methylation pathway: the bulk genome is demethylated and promoters of specific genes become aberrantly hypermethylated (11
,12
). In the case of CpG islands found in gene promoters, there is a very strong positive correlation between transcriptional repression of the promoter and its hypermethylation.
Before discussing recent advances in understanding how methylation causes transcriptional repression, it is important to appreciate a critical functional compartmentalization of DNA methylation-based genome control. In normal development (as contrasted with cancer), the overwhelming majority of genes are not regulated by DNA methylation and its function is largely to keep repetitive DNA in check (13
). An important exception is a relatively small (100 is probably an overestimate) group of genes that are monoallelically expressed—transcription of such "imprinted" genes is controlled in part by differentially methylated regions (DMRs), thus named because the difference in methylation status of the DMR on maternally versus paternally derived chromosomes determines which allele is actually expressed (14
). Another important group of genes controlled by methylation is that located on the inactive X chromosome of female mammals (15
).
DNA methylation and chromatin: a web of connections.
How does methylation of a CpG island in a gene promoter silence its transcription? Some transcription factors cannot bind methylated targets, and it is possible that such "activator exclusion" contributes to methylation-driven repression. In addition, a complex integration is thought to exist between the DNA methylation machinery and chromatin-based regulatory pathways (16
). This phenomenon is incompletely understood and at present largely represents an array of biochemically established connections, some more tenuous than others.
The first connection between methylation and chromatin is provided by the enzyme that converts cytosine to 5-methylcytosine, DNA (cytosine-5)-methyltransferase (Dnmt; EC 2.1.1.37). Mammalian genomes contain at least three genes that produce catalytically active Dnmt (1, 3a and 3b) (17
). It was surprising to find that proteins involved in covalently modifying DNA interact with proteins that covalently modify chromatin—the histone deacetylases (HDACs). Biochemical analysis of Dnmt1 showed that it associates with the enzyme HDAC1 (18
,19
). Biochemical evidence suggested that Dnmt1 can also interact with a related enzyme, HDAC2 (20
). Subsequent analysis showed that Dnmt3a can associate with HDAC1 as well (21
). In an important test, it was shown that both Dnmt1 (18
–20
) and Dnmt3a and Dnmt3b (21
,22
) possess transcriptional repression properties that are independent of their DNA methyltransferase activity (22
) and depend on HDAC for function.
These biochemical data are interesting, but it is at present unclear how to integrate them into the current understanding of Dnmt function. HDACs are an important class of genome behavior regulators—they catalyze the removal of acetyl moieties from 
-amino functional group (-NH2) groups of lysine residues in the core histone tails (23
,24
). Histone tail lysine acetylation is found in all eukaryotic taxa, where it has been studied and is a major pathway of genome control (25
). Typically, loci that are transcriptionally active are associated with hyperacetylated histones, whereas loci that are repressed are associated with deacetylated histones. This correlation is well established and is buttressed by the extensive integration of histone acetyltransferases (HATs) into pathways of transcriptional activation (26
) and, conversely, of HDACs—into pathways of transcriptional repression (24
). Although it is clear that changes in chromatin acetylation cause changes in transcriptional activity, it is less clear how to explain this chain of causality in terms of mechanism (27
). The process may involve regulating transcription factor access to DNA, higher order chromatin folding or the binding of regulatory factors that possess acetyl-lysine binding domains to acetylated chromatin (28
).
The biochemical connection between Dnmt and HDAC is consistent with the repressive effects of DNA methylation on transcription and with HDAC involvement in repression pathways. It is possible that, in addition to the known role for Dnmt in recreating the epigenetic mark on DNA in the wake of DNA replication fork passage, Dnmt also contributes to establishing a repressive chromatin architecture on methylated DNA by targeting HDAC (Fig. 1
). The temporal order of these phenomena—i.e., when exactly in the wake of DNA replication Dnmt methylates nascent hemimethylated DNA and at what point the HDAC that it targets acts on the adjacent chromatin—remains unexplored.
|
). There are at least four proteins coded for by the human genome that selectively recognize methylated DNA: methyl-CpG-binding protein 2 (MeCP2), methyl-CpG-binding domain protein 1 (MBD1), and methyl-CpG-binding domain protein 2 (MBD2), and Kaiso. The MBDs and MeCP2 share an unusual property thought to result from the relatively small DNA binding surface they contain (30
,31
): they can bind to methylated DNA when it is wrapped around a histone octamer (32
). This implies that repressed chromatin that forms over hypermethylated DNA loci may also contain, in addition to the histones, methylated DNA binding proteins that would, in effect, be "standing guard" over that DNA.
The second connection between chromatin and methylation is provided by, once again, biochemical observations: it was discovered that MeCP2 associates with HDAC activity and represses transcription in a manner that is sensitive to small-molecule HDAC inhibitors (33
,34
)—incidentally, both features characterize a great number of different transcriptional repressors in all eukarya studied (23
). Together with the Dnmt-HDAC connection described earlier, these data yield a simple model in which HDAC targeting persists at a methylated locus. The scenario is thought to involve Dnmts recruiting HDAC in the wake of replication fork passage to achieve immediate repressive action; this is followed by the MBDs binding to the methylated DNA, which targets HDAC to protect the locus from spurious reactivation.
Appealing in its simplicity, this model will soon be expanded to accommodate two observations that it currently fails to account for:
). For example, although MeCP2 is broadly distributed throughout the nucleus (35
), mice lacking MeCP2 develop a phenotype that seems to be central nervous system (CNS)-specific (36
,37
). Strikingly, some of the symptoms exhibited by the MeCP2 null animals resemble those observed in human patients with Rett syndrome, a sex-linked disorder caused by mutations in MeCP2 (38
). This apparent conservation of function of MeCP2 fails to explain, however, why the animals lacking such function live to 6 wk with no macroscopic developmental abnormalities and thus do not phenocopy animals lacking Dnmt function; knockout animals for some Dnmts do not even survive embryogenesis (39
,40
). Other methylated DNA binding proteins may compensate for MeCP2 function, or non-MBD-based mechanisms for repressing transcription over methylated DNA loci may exist.
,34
). In stark contrast, transcription of a gene silenced by methylation cannot be activated by TSA treatment (41
). This important observation illuminates the existence of auxiliary, non-HDAC-based pathways of repressing transcription from methylated DNA templates.
The third connection between methylated DNA and chromatin is the most tantalizing and also the least explored from a functional sense; it is provided by the Mi-2 complex (42
). It was discovered (43
) in frog egg extracts—a well established source of biological material for biochemical investigation—as a multisubunit union between an ATPase called Mi-2 (hence the name of the complex) and an HDAC. Mammalian versions of the Mi-2 complex were subsequently described to possess chromatin remodeling activity (44
,45
), which led to its rather homophonically awkward designation "NuRD," for nucleosome remodeling and deacetylation.
Although the Mi-2 complex is exceedingly abundant and conserved in metazoa, including Drosophila melanogaster (46
–48
), its in vivo function remains a mystery. Genetic analysis in D. melanogaster indicates that it contributes to transcriptional repression by Polycomb group proteins (48
). The Mi-2 complex is hypothesized to have some function in repression in other organisms—including mammals—but conclusive data on that subject are scarce. There is evolutionary precedent for a synergy between an ATPase and an HDAC in driving repression (49
), as well as extensive evidence indicating that chromatin ATPases act as repressors in vivo (50
–52
)—all these data, however robust and conclusive, come from budding yeast. A different ATPase complex, SWI/SNF, is required for repression by the retinoblastoma protein (53
,54
).
In addition to the ATPase and the HDAC, the Mi-2 complex contains four other subunits, including the protein MBD3. In Xenopus laevis, this protein binds methylated DNA selectively, but the mouse ortholog contains a tyrosine-phenylalanine (Tyr-Phe) transition in a position critical for 5-methylcytosine recognition and thus does have binding preference for methylated DNA (31
,55
,56
). These are not esoteric issues of structural biology—rather, this addresses a key problem: how the Mi-2 complex is targeted to the loci where it functions. In mammals, it has been suggested that such targeting to methylated DNA occurs via the protein MBD2. It is proposed that MBD2 binds methylated DNA and then recruits the Mi-2 complex (57
). It is not known which, if any, endogenous methylated DNA loci are affected by Mi-2 function. If such loci exist, then the resistance of transcriptional repression over hypermethylated promoters to HDAC function may therefore be explained by a synergy between the ATPase and the HDAC in achieving repression. In yeast, a transcriptional repressor that targets both an ATPase and an HDAC is able to sustain a considerable proportion of repressive function even when the gene coding for the HDAC has been deleted (49
). Use of designed transcription factors based on the zinc finger protein motif (58
,59
) to activate genes silenced by methylation also reveals complex functional redundancy in methylation-driven repression (Raschke, E., Lai, A., and Kunis, M., unpublished observations).
Protein methylation and the genome.
In addition to the modification of DNA by methylation, many protein constituents of the nucleus are methylated as well (4
). With respect to components of chromatin, it has been known since 1964 that histones are methylated in vivo (60
,61
). As was the case with the other cause célèbre of genome biology in the 1990s, histone acetylation, the rise of methylation to prominence had to wait until the identification of enzymes that methylate proteins and, more importantly, until data were available that connected these enzymes to specific genome regulatory pathways.
The year 1999 saw a very exciting scientific development: an arginine methyltransferase, coactivator-associated arginine methyltransferase 1 (CARM1), was shown to function as a coactivator for such liganded nuclear hormone receptors as thyroid hormone receptor, androgen receptor and the estrogen receptor (62
)—the term "coactivator" refers to a large, diverse group of protein factors that are targeted by various DNA-bound regulators to up-regulate transcription. Well characterized coactivators for the nuclear hormone receptor superfamily include such HATs as cyclic adenosine 5' -monophosphate response element-binding protein (CREB) binding protein (CBP)/p300 and steroid receptor coactivator 1 (SRC-1) (63
,64
). CARM1 seems to selectively methylate specific arginine residues within histone H3. Importantly, mutational analysis established a strong positive correlation between the enzymatic and coactivator functions of CARM1 (62
). A different arginine methyltransferase, predominant cellular arginine N-methyltransferase of type 1 (PRMT1), that acts on arginine 3 in the histone H4 tail, was recently also shown potentiate transcriptional activation by nuclear hormone receptors (65
–67
).
The molecular mass of a methyl group is only 15 Da. In contrast, the combined molecular masses of all the coactivators and components of the basal transcription machinery, the activity of which is controlled by a liganded nuclear hormone receptor, easily exceeds 1500 kDa. How can such a physically slight modification of chromatin over target promoters have an effect on entities 5 orders of magnitude its size?
Hints of an answer were provided by analysis of a different class of methyltransferases, the SET-domain histone methyltransferases (HMTases). In addition to providing a framework to begin to explain how histone methylation affects genome behavior, these studies also offer an explanation of how methylation of different residues within the same histone can have diametrically opposite functional consequences for the DNA locus bound into chromatin modified in a particular way. The SET domain is shared by a number of proteins involved in gene control, including D. melanogaster proteins Su(var)3–9 (68
), the polycomb-group protein E(z) and the trithorax protein. In the year 2000, a key experiment provided the first glimpse of what subsequently became one of the biggest discoveries in the biology of chromatin and genome control of the past decade: the laboratory of T. Jenuwein showed that overexpression of the mouse homolog of the D. melanogaster Su(var)3–9 protein in tissue culture cells has a remarkable effect: it massively redistributes the heterochromatin protein 1 (HP1) protein within the nucleus (69
). HP1 is a major protein component of chromatin assembled over the largely transcriptionally inactive fraction of the genome—heterochromatin. The mechanism whereby HP1 becomes targeted to specific loci remained obscure.
One explanation of the data shown by Melcher and colleagues (69
) was that mouse Suv39h1 somehow determines which chromatin loci become bound by HP1. It was then observed by computational analysis that the SET domain has limited primary sequence and secondary structure similarity to certain plant methyltransferases (70
– 72
). Importantly, subsequent analysis showed that the similarity extends into function and that the Suv39h1 protein is, indeed, an HMTase that selectively methylates lysine 9 in the histone H3 amino-terminal tail (73
). The discovery that completed this particular jigsaw puzzle was the finding that a particular region within the HP1 protein—the chromodomain—acts as a high-affinity binding module for the histone H3 tail methylated on lysine 9 (74
,75
). This was particularly exciting because it illuminated a simple mechanism for the epigenetic stability of heterochromatin in the face of DNA replication and cell division (3
): core histones from the mother chromatid are known to randomly segregate onto the nascent daughter strands in the wake of replication fork passage (76
)—HP1 that is attached to its histone code lure of histone H3 methylated on lysine 9, and HP1’s attending repressive entourage (77
), would thus all be expected to segregate to the daughters as some sort of "molecular dowry" that recreates on the nascent DNA the functional state that chromatin was in on the mother chromatid (Fig. 1)
.
SET domain HMTases are the focus of much current research; this is a rapidly developing field. Thus, only a few general points can be made that may not remain unamended for long by subsequent data. There seems to be a strong correlation between stretches of chromatin in which histone H3 is methylated on lysine 9 and transcriptional repression (78
,79
). There are a considerable number of SET domain proteins in the human genome—genetic data implicate Suv91h1 in maintaining methylation over pericentromeric heterochromatin (80
), indicating that some other HMTase is responsible for methylating histone H3 on lysine 9 over other stretches of the genome (for example, over the inactive X chromosome in female cells (81
). In addition to the arginine HMTases discussed earlier, it is possible that some SET domain HMTases may have roles in transcriptional activation—for example, those that methylate histone H3 on lysine 4 (82
).
The observation that a histone tail modified in a particular way assembled into chromatin over a DNA locus serves as the binding site for a protein that subsequently imposes onto that DNA a particular functional state was a strong confirmation of the "histone code" hypothesis (83
). The amino terminal tails of the various core histones are subjected to a variety of posttranslational modifications after they have been assembled into chromatin. Specific modifications seem to be associated with particular functional states—for example, as elaborated in the previous paragraph, if chromatin over a given locus contains histone H3 methylated on lysine 9, it is likely that this stretch of DNA will form heterochromatin. Conversely, hyperacetylated chromatin that is also methylated on lysine 4 within histone H3 is associated with transcriptionally active loci. The "histone code" idea proposes that the nucleus has a mechanism to "read" the pattern of chromatin modifications over a given locus and then impose onto the underlying DNA a functional state that is determined by that "code" (83
). The term "code" implies the existence of an " interpreter"—i.e., some mechanism whereby code word X is interpreted to mean functional state Y. The affinity of the chromodomain of HP1 for histone H3 methylated over lysine 9 is an excellent example of how such interpretation occurs in vivo. It is thus possible that other methylation states of chromatin—e.g., histone H3 methylated on lysine 4—have also been assigned a protein module that binds that state selectively and interprets this modification. Alternatively, it is possible that certain types of histone tail modifications affect the ability of that histone molecule to undergo other types of modification, and this has functional consequences (for example, chromatin hyperacetylated on lysine 9 in histone H3 is unlikely to be assembled into heterochromatin because that lysine residue cannot be methylated until the acetyl group is removed first).
Both for purposes of basic science and for more applied reasons, it would be beneficial to dissect the sequence of events that leads to, for example, promoter silencing by hypermethylation in cancer. Although there is no clear example in which all the events have been studied on one system, three very recent discoveries offer a glimpse of things to come. The first example illuminated an unexpected connection between histone and DNA methylation (84
); it was found that genomic DNA methylation in the filamentous fungus Neurospora crassa requires the action of an HMTase. This suggested a model in which histones over a given locus are methylated first, and this modified chromatin somehow recruits a de novo DNA methyltransferase—incidentally, the plant Arabidopsis thaliana has a Dnmt gene that contains a chromodomain [this protein has been dubbed a " chromomethylase" (85
)]. Tamaru and Selker describe this as a situation in which "some DMTases take cues directly from the histones." Whether the human genome contains a hitherto undiscovered chromomethylase remains to be seen, of course. Secondly, Jacobsen and colleagues (86
) report that an H3K9 HMTase is required for DNA methylation in A. thaliana—very strong genetic arguments based on analysis of gene epistasis indicate the HMTase creates a binding surface for HP1 (as in mammals), which then recruits a Dnmt, and the underlying DNA is then methylated. This work is of exceptionally high quality, but it is essential to exercise caution before extrapolating these data—obtained in plants that contain a chromodomain-Dnmt that mammals do not—to any animal system, especially humans, where epistasis analysis is currently very difficult. The third discovery is a very recent report (87
) that the leukemic fusion protein promelocytic leukemia-retinoic acid receptor (PML-RAR) recruits DNA methyltransferase to the promoter of the retinoic acid receptor ß (RARß) gene and causes it to be de novo hypermethylated and silenced. This is the first published observation of the targeting of a Dnmt to an endogenous promoter in human cells via a DNA-bound transcription factor. The simple model suggested by this finding is that PML-RAR targets Dnmt and HDAC (88
), which leads to histone deacetylation and DNA hypermethylation. The deacetylated histones then, one presumes, become available for subsequent enzymatic modifications (e.g., methylation). As can be seen, these two discoveries offer two very different scenarios of the sequence of events that leads to DNA methylation-based repression—it is possible that multiple distinct pathways are evoked by the human genome during this process.
Future directions.
An important, currently untested prediction of all the recent data on protein/DNA methylation and genome control is that dietary imbalance affecting methylation-based pathways may have a broader effect on the genome than previously thought. The causes of a considerable proportion of human diseases can be traced to the misregulation of genome behavior—transcription or chromosome segregation and stability, for example. Awareness of the extensive role that protein methylation plays in genome control is too recent, however, to connect, for example, folate deficiency in the diet of expectant mothers to an increased risk of spina bifida in their children via the failure to properly methylate a transcription factor or a component of chromatin required for correct expression of genes involved in neural tube formation. The extraordinary recent expansion of various genome-wide analysis technologies—for example, the ability to profile the genome’s transcriptional response to a given stimulus while being able to obtain genomewide information about DNA methylation status and protein binding in vivo (89
–93
)—offers promise of new insights on the connection between biochemical pathways of methyl metabolism and genome control.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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3 Abbreviations used: CARM1, coactivator-associated arginine methyltransferase 1; CBP/p300, CREB binding protein; CG, cytosine guanine; CNS, central nervous system; CpG, cytosine guanine dinucleotide; CREB, cyclic adenosine 5'-monophosphate response element-binding protein; DMRs, differentially methylated regions; Dnmt, DNA (cytosine-5)-methyltransferase; GC, guanine cytosine; HATs, histone acetyltransferases; HDACs, histone deacetylases; HMTases, histone methyltransferases; HP1, heterochromatin protein 1; MBD, methyl-CpG-binding domain protein; MeCP2, methyl-CpG-binding protein 2; NuRD, nucleosome remodeling and deacetylation; PML-RAR, promelocytic leukemia-retinoic acid receptor; PRMT1, predominant cellular arginine N-methyltransferase of type 1; RARß, retinoic acid receptor ß; SRC-1, steroid receptor coactivator 1; TSA, trichostatin A; Tyr-Phe, tyrosine-phenylalanine.
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LITERATURE CITED |
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TOPABSTRACTINTRODUCTIONDISCUSSIONLITERATURE CITED |
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