Histone modifications play at least two roles in the establishment of the epigenetic landscape of a cell. They can act as heritable repressive marks that compact chromatin and inhibit transcription of specific genes or loci, but they can also focus DNMTs to chromatin, thus establishing the more stable epigenetic mark CpG methylation. In general, regions permissive for transcription have ‘open’ active chromatin, marked by hyperacetylation of histones H3 and H4 at multiple sites and trimethylation of histone H3 at lysine 4 (H3K4me3, not shown). HDAC remove acetyl groups (Ac) from H3 and H4, and at least two complexes initiate further repressive histone modifications. (a) Complexes containing one or both of the histone methyltransferases G9a and SUV39H1 are responsible for trimethylation of H3 at lysine 9 (H3K9me3), establishing chromatin in a ‘closed’ repressive state. H3K9me3 then recruits the heterochromatin-protein HP1 to form heterochromatin; G9a, SUV39H1, HDACs and HP1 are all capable of binding and recruiting DNMTs, which can then facilitate CpG methylation ([89–92] and references therein). Methyl cytosines established by the DNMTs serve as docking sites for methyl-CpG binding domain (MBD) proteins such as MeCP2. (b) Polycomb-mediated repression facilitates a second repressive modification. PRC2 is composed of SUZ12, EED and the H3 lysine 27 methyltransferase EZH2, which establishes the H3K27me3 mark. H3K27me3 recruits PRC1, which includes BMI1 and RING1B and is responsible for the additional repressive modification of ubiquitinylation of histone H2A at lysine 119 (H2AK119Ub, not shown). Components of PRC1 (BMI1) and PRC2 (EZH2) and HDACs physically associate with DNMTs and also provide a platform for CpG methylation [4,6,82]. Again, MBD proteins such as MeCP2 bind and consolidate the repression or silencing.