The Histone Variant H3.3 in Transcriptional Regulation and Human Disease

Abstract

Histone proteins wrap around DNA to form nucleosomes, which further compact into the higher-order structure of chromatin. In addition to the canonical histones, there are also variant histones that often have pivotal roles in regulating chromatin dynamics and in the accessibility of the underlying DNA. H3.3 is the most common non-centromeric variant of histone H3 that differs from the canonical H3 by just 4-5 aa. Here, we discuss the current knowledge of H3.3 in transcriptional regulation and the recent discoveries and molecular mechanisms of H3.3 mutations in human cancer.

Keywords: DAXX; H3.3; HIRA; epigenetics; human cancer.

Figure 1. Protein sequence, genomic distributions, and cancer mutations of H3.3

Amino acids in H3.3 that are distinct from canonical H3 are shown in blue squares and highlighted with residue numbers. G90 is an essential amino acid recognized by UBN1 in the HIRA complex or DAXX in the DAXX/ATRX, the two known variant-specific chaperones that deposit H3.3 into distinct chromosomal regions that is highlighted in different colors in the schematic representation of chromosome. Amino acids that are mutated in human cancers are shown in red squares and highlighted with residue numbers. Mutation of K27M or K36M inhibits the enzymatic activity of EZH2 or SETD2, respectively, leading to global loss of H3K27 methylation in DIPG or H3K36 methylation in chondroblastoma. The mechanism of G34 mutations to various amino acids is current not clear. Abbreviations: A: alanine; G: glycine; I: isoleucine; K: lysine; L: leucine; M: methionine; R: arginine; S: serine; DIPG: diffuse intrinsic pontine glioma; GCTB: giant cell tumors of the bone; GBM: glioblastoma.