Random deposition of histone variants: A cellular mistake or a novel regulatory mechanism?

Abstract

Despite the fact that it has been intensively studied during the last decade, the function of the histone variant H2A.Z remains enigmatic. In the last few years, we and others have determined the localization of H2A.Z in various organisms. These studies have revealed that H2A.Z occupies different well defined regions in the genome. Interestingly, H2A.Z occupies the promoters and regulatory regions of active genes, as well as constitutive and facultative heterochromatin. The localization of H2A.Z on genomic regions with so diverse functions suggests that the roles of H2A.Z are multiple, only increasing the mystery around this molecule. The way H2A.Z finds its way into these regions is not fully understood but mechanisms that direct the specific incorporation of H2A.Z in promoters and enhancers have been well described. In this Point of View, we review our recent work suggesting that non-targeted incorporation, coupled to targeted depletion of H2A.Z, is a novel mechanism for localizing H2A.Z to some regions. We propose that the various functions of H2A.Z may be a consequence of the mechanism used for its incorporation, as well as its interactions with other histone variants.

Dual Role of the Histone Variant H2A.Z in Transcriptional Regulation of Stress-Response Genes

“…It is important to emphasize that we did not find evidence for a redistribution of H2A.Z, which could occur via a hypothetical arp6-independent H2A.Z deposition pathway (Jeronimo et al, 2015) ( Figure 6C; Supplemental Figure 10) or passive H2A.Z incorporation during nucleosome reassembly (no correlation with expression rate was observed) (Hardy and Robert, 2010). This indicates that the SWR1 complex is the major factor controlling spatial distribution of H2A.Z in chromatin in plants.…”

Histone Variants and Epigenetics

“…In budding yeast, nematodes, and plants, H2A.Z occupancy around the promoter is correlated with nontranscribing genes "poised" for activation (Zhang et al 2005;Mavrich et al 2008;Whittle et al 2008;Kumar and Wigge 2010). However, in flies and mammals, promoter H2A.Z occupancy appears to correlate more with actively transcribing genes (Barski et al 2007;Mavrich et al 2008;Hardy et al 2009;Hardy and Robert 2010;Kelly et al 2010), similar to the situation for H3.3. Although preferentially found at promoters and regulatory sites, H2A.Z nucleosomes can also be found at lower frequency in gene bodies and elsewhere Weber et al 2010;Santisteban et al 2011).…”

“…The S. pombe SWR1 complex contains a regulatory subunit, Msc1, which is dispensable for the loading of H2A.Z at promoter nucleosomes, but which is required to prevent H2A.Z deposition within the chromatin of the inner centromere and subtelomeric regions (Buchanan et al 2009;Zofall et al 2009). It has also been suggested that an additional pathway directing localized occupancy by H2A.Z may involve its random deposition and then specific eviction, perhaps as a consequence of transcription (Hardy and Robert 2010).…”

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

“…Three non-mutually exclusive mechanisms can be envisioned. Firstly, H2A.Z can be actively incorporated at specific sites by targeting factors; secondly, H2A.Z can be randomly incorporated and afterwards (actively) removed from non-target sites (103) and thirdly, H2A.Z localization can be explained by differential stabilities of homotypic H2A.Z nucleosomes compared with heterotypic or canonical ones (81) [for recent reviews on H2A.Z deposition see (90,91,103)].…”