Histone variants on the move: substrates for chromatin dynamics

Key Points Histone variants replace canonical histones to carry out diverse roles in replication, transcription and heterochromatin formation, all of which are mediated by the activity of chaperones, chromatin remodellers and histone-modifying enzymes. Some chaperones have evolved to distinguish between histone variants and canonical histones and direct them into specialized assembly pathways, whereas other chaperones process variants and canonical histones similarly. The MCM2 subunit of the replication helicase does not distinguish between canonical H3 and its variants, and may pass different H3 variants as well as post-translationally modified H3 from the front to the back of the replication fork. By contrast, new nucleosomes comprising canonical histones are deposited behind the fork by the chaperone chromatin assembly factor 1 (CAF1), which excludes H3 variants. H2A.Z has a conserved role in transcription initiation, which nevertheless varies between organisms and contexts. H2A.Z is found flanking promoters and in some enhancers and can recruit RNA polymerase II, but is then evicted by the transcription machinery. Other H2A variants — H2A.B and macroH2A — can occupy specific promoters in specific cell types. H2A.B, which wraps only ∼120 bp of DNA, appears to facilitate transcription, whereas macroH2a may reinforce active or repressed expression states. H3.3 has high turnover rates at regulatory elements such as enhancers. HIRA deposits H3.3 in gene bodies to replace nucleosomes evicted during transcription, whereas ATRX–DAXX (alpha thalassemia mental retardation syndrome X-linked–death domain associated protein) complex deposits H3.3 into heterochromatin, where it is necessary for maintaining H3 Lys9 trimethylation and preventing transcription of silenced repetitive elements. H2A.Z is necessary for the maintenance of heterochromatin in animals, possibly because chaperones for canonical H2A are not active in heterochromatin outside of S phase. In plants, H2A.W, which wraps 162 bp of DNA, is necessary for heterochromatin condensation. Histone variants are typically incorporated into chromatin independently of DNA replication and modify chromatin properties. Recent studies have elucidated how particular histone variants are substrates of histone chaperones, chromatin remodellers and histone-modifying enzymes, thereby modifying DNA replication and repair, transcription and chromatin packaging. Most histones are assembled into nucleosomes behind the replica