Short Histone H2A Variants: Small in Stature but not in Function

Abstract

The dynamic packaging of DNA into chromatin regulates all aspects of genome function by altering the accessibility of DNA and by providing docking pads to proteins that copy, repair and express the genome. Different epigenetic-based mechanisms have been described that alter the way DNA is organised into chromatin, but one fundamental mechanism alters the biochemical composition of a nucleosome by substituting one or more of the core histones with their variant forms. Of the core histones, the largest number of histone variants belong to the H2A class. The most divergent class is the designated "short H2A variants" (H2A.B, H2A.L, H2A.P and H2A.Q), so termed because they lack a H2A C-terminal tail. These histone variants appeared late in evolution in eutherian mammals and are lineage-specific, being expressed in the testis (and, in the case of H2A.B, also in the brain). To date, most information about the function of these peculiar histone variants has come from studies on the H2A.B and H2A.L family in mice. In this review, we describe their unique protein characteristics, their impact on chromatin structure, and their known functions plus other possible, even non-chromatin, roles in an attempt to understand why these peculiar histone variants evolved in the first place.

Widespread formation of double-stranded RNAs in testis

“…On the other hand, the minor bias toward overexpression of a heterogeneous (small) group of genes in KO animals is consistent with a role for DICER1 in processing dsRNA. Of note, DICER1 is localized to the chromatoid body in spermatocytes and round spermatids where also most of the polyadenylated RNA is accumulated (Kotaja et al 2006;Jiang et al 2020). A related observation was also made by Zimmermann and coworkers who reported a small up-regulation of protein-coding genes in Dicer1 KO animals (Zimmermann et al 2014).…”

Short H2A histone variants are expressed in cancer

“…Short histone H2A variants (sH2A) are a class of histone variants expressed during mammalian spermatogenesis [8][9][10][11] . Regulation of sH2A expression in normal testis is unknown 12 . Unlike other histone variants, sH2As are rapidly evolving and possess highly divergent HFDs, mutated acidic patches, and truncated Ctermini, all of which impact nucleosome stability 8,[13][14][15][16] .…”

H2A.B is a cancer/testis factor involved in activation of ribosome biogenesis in Hodgkin Lymphoma

“…Among the core histones, the H2A family shows the greatest divergence in their primary sequence leading to the largest number of variants known. These variants include H2A.Z, H2A.X, MacroH2A, H2A.J, H2A.R and the “short histone” variants H2A.B, H2A.P, H2A.L and H2A.Q (Jiang et al, 2020; Malik and Henikoff, 2003; Molaro et al, 2018; Talbert and Henikoff, 2010). Key amino acid residue differences between the canonical histone H2A and its variant forms are strategically placed within the nucleosome and on its surface, and these differences affect nucleosome stability, higher-order chromatin compaction, and the interaction with reader proteins (Buschbeck and Hake, 2017; Doyen et al, 2006; Fan et al, 2004; Luger et al, 2012; Martire and Banaszynski, 2020; Shaytan et al, 2015; Zhou et al, 2007).…”

“…The short histone variants, designated as “short” because they lack an H2A C-terminus, are the most divergent. These histone variants appeared late in evolution in eutherian mammals, and are lineage-specific being expressed in the testis (Jiang et al, 2020; Molaro et al, 2018). The testis-specific expression of mouse H2A.B (H2A.B.3) is developmentally regulated with the peak of its expression occurring in highly transcriptionally active haploid round spermatids (the stage before transcription is switched off) (Anuar et al, 2019; Soboleva et al, 2012; Soboleva et al, 2014; Soboleva et al, 2017).…”