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

C Bonisch,S B Hake

doi:10.1093/nar/gks865

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.

Highlights

In eukaryotes, DNA is organized into chromatin to fit into the constrained space of the nucleus
These findings are in perfect agreement with data from us [20] and others [21], showing that Z.2.2 messenger RNAs (mRNAs) is normally low abundant but constitutes up to 50% of the H2A.Z.2 isoforms in brain tissues
H2A.Z’s extended acidic patch is not the sole determinant here, as it is required but not sufficient for stimulation of remodelling activity. Whole complexes, such as ACF, can overcome this requirement. These results suggest that alterations of the acidic patch in H2A variants could confer different properties to chromatin by more indirect means, by influencing chromatin structure and altering interactions with different proteins, and by changing activities of chromatin factors that act on them, like adenosine triphosphate (ATP)-dependent chromatin remodelling complexes

Summary

INTRODUCTION

DNA is organized into chromatin to fit into the constrained space of the nucleus. Both H2A.Z proteins can be acetylated at the same N-terminal lysine residues [Figure 3 and [110]], and they show similar nuclear localization patterns [20,110] and fluorescence recovery after photobleaching (FRAP) mobilities [20] Their promoter structures, are different between both genes [110], and knock-out of H2A.Z.2 but not of H2A.Z.1 leads to BCL6 downregulation and increased apoptosis in chicken DT40 cells, suggesting functional (sub)specialization of the two H2A.Z variants [112]. The H2A family has a multitude of different members that differ strikingly with regards to their evolutionary conservation, amino acid sequences and domain architectures, and the biological processes they play roles in The mechanisms of their functions are often not well understood; open questions remain, including how they are targeted to their respective chromatin sites, and how specific interaction partners contribute to their biological roles. To note that evidence found by analysing ATP-dependent chromatin remodelling of H2A variant nucleosomes in vitro must be complemented with suitable in vivo studies, as in vivo chromatin’s properties are too complex to be reflected completely by chromatin assembled in vitro

CONCLUDING REMARKS

Findings

Literature Relevant domains