Linking DNA methylation and histone modification: patterns and paradigms

Key Points

  • The basic pattern of genomic DNA methylation is established at the time of embryo implantation through a wave of de novo methylation, but CpG islands are protected through a mechanism that involves the recognition of histone H3 lysine 4 methylation.

  • DNA methylation and histone modification influence each other during development. Histone methylation can help to direct DNA methylation patterns, and DNA methylation seems to serve as a template for rebuilding histone modification patterns following DNA replication.

  • Targeted de novo methylation during development involves SET domain-containing proteins that are capable of specifically methylating histones as well as recruiting DNA methyltransferases.

  • Targeted gene silencing can be mediated by repressor complexes, heterochromatinization and DNA methylation. DNA methylation may be a secondary event that provides long-term stability.

  • During reprogramming of somatic cells, pluripotency genes become reactivated in a process that involves changes in histone modification followed by demethylation of the DNA.

  • De novo methylation in cancer is probably targeted to some genes marked with histone H3 lysine 27 methylation.


Both DNA methylation and histone modification are involved in establishing patterns of gene repression during development. Certain forms of histone methylation cause local formation of heterochromatin, which is readily reversible, whereas DNA methylation leads to stable long-term repression. It has recently become apparent that DNA methylation and histone modification pathways can be dependent on one another, and that this crosstalk can be mediated by biochemical interactions between SET domain histone methyltransferases and DNA methyltransferases. Relationships between DNA methylation and histone modification have implications for understanding normal development as well as somatic cell reprogramming and tumorigenesis.

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Figure 1: Establishment of bimodal methylation.
Figure 2: Turning off pluripotency genes.
Figure 3: SET domain-containing histone methyltransferases interact with DNMT3A and DNMT3B.
Figure 4: A model of somatic cell reprogramming.
Figure 5: A model of de novo methylation in cancer.


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This work was supported by grants from the Israel Academy of Science (Y.B. and H.C.), the National Institutes of Health (Y.B. and H.C.), the Israel Cancer Research Fund (Y.B. and H.C.) and Lew Sherman (H.C.).

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Correspondence to Howard Cedar.

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Protein component of chromatin that is involved in regulation of gene expression. Two of each of the core histones, H2A, H2B, H3 or H4, make up an octameric nucleosome, around which DNA winds. N-terminal tails of histones can be subject to covalent modification, including methylation and acetylation.

CpG island

A sequence of at least 200 bp with a greater number of CpG sites than expected given the average GC content of the genome. These regions are typically undermethylated and are found upstream of many mammalian genes.


Initially identified in the Drosophila melanogaster heterochromatin protein 1 and Polycomb proteins, this is an 50 amino acid, highly conserved domain that binds to histone tails that are methylated at certain lysine residues. Different classes of chromodomains have been implicated in binding histones, RNA and DNA.

Heterochromatin protein 1

(HP1). Conserved component of silent heterochromatic regions, which contains a chromodomain that binds nucleosomes containing histone H3 that is methylated on lysine 9.


Highly compacted regions of chromatin, in which transcription is repressed. Constitutive heterochromatin is a common feature of highly repetitive DNA sequences.

Satellite repeat

DNA that contains many tandem repeats of a short basic repeating unit. Both the major and minor satellite repeats are located at pericentromeric heterochromatin.

SET domain

An evolutionarily conserved sequence motif that was initially identified in the Drosophila melanogaster position effect variegation suppressor Su(var)3–9, the Polycomb-group protein Enhancer of zeste, and Trithorax (a Trithorax group protein). It is present in many histone methyltransferases and is required for enzyme activity.


An RNA endonuclease that cleaves double-stranded RNA into small interfering RNAs of approximately 21 bp.

RNA-induced silencing complex

(RISC). A complex made up of an Argonaute protein and small RNA, which inhibits translation of target RNAs through degradative or non-degradative mechanisms.

Imprinted locus

A locus at which the expression of an allele is different depending on whether it is inherited from the mother or the father.

X chromosome inactivation

The process that occurs in female mammals by which gene expression from one of the two X chromosomes is downregulated to match the levels of gene expression from the single X chromosome that is present in males. Inactivation involves changes in DNA methylation and histone modifications.

Chromatin immunoprecipitation

(ChIP). A technique that is used to analyse the genomic location of DNA-associated proteins that involves crosslinking DNA–protein complexes then immunoprecipitation using an antibody against a protein of interest. This is followed by analysis of the recovered DNA sequences.

Polycomb repressive complex

(PRC). A group of repressive chromatin proteins that maintain states of gene expression throughout development. Originally identified in Drosophila melanogaster as genes in which mutations caused homeotic transformations.

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Cedar, H., Bergman, Y. Linking DNA methylation and histone modification: patterns and paradigms. Nat Rev Genet 10, 295–304 (2009).

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