Histone H2A variants in nucleosomes and chromatin: more or less stable?

Abstract

In eukaryotes, DNA is organized together with histones and non-histone proteins into a highly complex nucleoprotein structure called chromatin, with the nucleosome as its monomeric subunit. Various interconnected mechanisms regulate DNA accessibility, including replacement of canonical histones with specialized histone variants. Histone variant incorporation can lead to profound chromatin structure alterations thereby influencing a multitude of biological processes ranging from transcriptional regulation to genome stability. Among core histones, the H2A family exhibits highest sequence divergence, resulting in the largest number of variants known. Strikingly, H2A variants differ mostly in their C-terminus, including the docking domain, strategically placed at the DNA entry/exit site and implicated in interactions with the (H3–H4)2-tetramer within the nucleosome and in the L1 loop, the interaction interface of H2A–H2B dimers. Moreover, the acidic patch, important for internucleosomal contacts and higher-order chromatin structure, is altered between different H2A variants. Consequently, H2A variant incorporation has the potential to strongly regulate DNA organization on several levels resulting in meaningful biological output. Here, we review experimental evidence pinpointing towards outstanding roles of these highly variable regions of H2A family members, docking domain, L1 loop and acidic patch, and close by discussing their influence on nucleosome and higher-order chromatin structure and stability.

Distinct features of lamin A-interacting chromatin domains mapped by ChIP-sequencing from sonicated or micrococcal nuclease-digested chromatin

“…36 Several studies also involve H2A.Z in the relaxation of chromatin, explained by instability of H2A.Z-containing nucleosomes. 37,38 Altogether, this provides a logic for H2A.Z detection in MNase LiDs. Additionally, although H2A.Z is positively involved in transcription, 30,[38][39][40] it also localizes to poised promoters bound by the Polycomb repressor 2 complex.…”

Histone variants: dynamic punctuation in transcription

“…Despite these structural differences, the change in the stability of the particle is subtle, with contrasting results reported. Overall, the consensus is that H2A.Z slightly stabilizes in vitro and destabilizes in vivo (Zlatanova and Thakar 2008;Bonisch and Hake 2012). This discrepancy might be attributable to post-translational modifications in vivo, where H2A.Z is acetylated at active genes (Bruce et al 2005;Valdes-Mora et al 2012); differences in DNA sequence; or the fact that H2A.Z nucleosomes can be hybrid in vivo, either heterotypic (Z/A) or homotypic (Z/Z) (Viens et al 2006;Luk et al 2010;Weber et al 2010).…”

Chromatin features and the epigenetic regulation of pluripotency states in ESCs

“…Histone variants are also subjected to different posttranslational modifications and as such could be selectively deployed to alter local epigenetic configuration through replacement of canonical histones at any point during the cell cycle (Hake et al, 2006;Loyola et al, 2006;McKittrick et al, 2004). When incorporated, histone variants can alter the overall stability of the nucleosome particle, regulating nucleosome turnover at key regulatory elements in the genome (Bonisch and Hake, 2012;Chen et al, 2013c;Henikoff, 2008;Jin and Felsenfeld, 2007). Some histone variants have also evolved highly specialized functions, whereas others are expressed in a tissuespecific manner (Talbert and Henikoff, 2010).…”