Constitutive and Facultative Heterochromatin

Cited from the Review "H3K9me3-Dependent Heterochromatin: Barrier to Cell Fate Changes"

A large fraction of mammalian genomes is taken up by repeat-rich sequences - including tandem-repeat satellites near centromeres and telomeres, retrotransposons, and endogenous retroviruses - which pose a risk to genome integrity through their potential for illicit recombination and self-duplication. Thus, in all cell types, there is utility in keeping such regions physically inaccessible and, consequently, transcriptionally silent, by packaging them in condensed heterochromatin. Such repeat-rich regions are classified as "constitutive" heterochromatin, as their silencing is universal across developmental lineages. By contrast, "facultative" heterochromatin refers to regions whose compaction and silencing is dynamic in development, such as at cell type-specific genes and enhancers.

In organisms ranging from the fission yeast Schizosaccharomyces pombe to humans, repeatrich constitutive heterochromatin is marked by dimethylation and trimethylation of histone 3 lysine 9 (H3K9me2 and H3K9me3).

In mammals, these covalent modifications are catalyzed by five members of the SET-domain containing family of methyltransferases. SETDB1 and the related enzymes SUV39H1 and SUV39H2 contribute to both H3K9me2 and H3K9me3, while GLP and G9a (also called EHMT1 and EHMT2, respectively) catalyze H3K9me1 and H3K9me2.

H3K9me2/me3 are bound by the chromodomain of Heterochromatin protein 1 (HP1, three isoforms in mammals), which can self-oligomerize and recruit repressive histone modifiers, contributing to heterochromatin compaction and spread.

The methyltransferases that deposit H3K9me2 and H3K9me3 are required to establish high levels of DNA methylation at CpG dinucleotides and low levels of histone acetylation, two other hallmarks of heterochromatin.

By contrast, cell type-specific repression of many genes requires trimethylation of a different H3 residue, lysine 27 (H3K27me3), which is catalyzed by the Polycomb repressive complex 2 (PRC2). This mode of ‘facultative’ silencing is particularly prominent at many lineage-specifying transcription factor genes, such as the homeobox (HOX) family.

The presence of H3K27me3 over gene promoters is highly correlated with gene repression , yet it has been shown that H3K27me3-marked promoters remain accessible to binding
by general transcription factors and a paused RNA polymerase.

This contrasts with chromatin marked by H3K9me3, which occludes the DNA from binding by transcription factors with diverse DNA-binding domains.

Although the H3K9me3 modification has been most often studied in the context of constitutive heterochromatin, genome-wide mapping studies have made clear its role in cell type-specific regulation of facultative heterochromatin. In differentiated human cells, H3K9me3 forms large contiguous domains ranging in size from the kilobase to the megabase scale. These domains or ‘patches’ expand in both number and size during differentiation from pluripotency, and they span numerous genes repressed in a cell typespecific manner. In particular, there is enrichment for H3K9me3 over gene family clusters, such as those for zinc finger transcription factors, olfactory receptors, and neurotransmitterrelated genes (in non-neuronal cell types), raising the possibility that H3K9me3 protects repetitive gene clusters from illicit recombination similar to noncoding repeats, while also suppressing transcription. Such H3K9me3 domains are largely exclusive of the H3K27me3  domains that also expand during development, highlighting the different functions of  these marks, although some developmental transcription factor genes are decorated by both  modifications.