Monoubiquitylation of H2A.Z Distinguishes Its Association with Euchromatin or Facultative Heterochromatin

Abstract

H2A.Z is a histone H2A variant that is essential for viability in organisms such as Tetrahymena thermophila, Drosophila melanogaster, and mice. In Saccharomyces cerevisiae, loss of H2A.Z is tolerated, but proper regulation of gene expression is affected. Genetics and genome-wide localization studies show that yeast H2A.Z physically localizes to the promoters of genes and functions in part to protect active genes in euchromatin from being silenced by heterochromatin spreading. To date, the function of H2A.Z in mammalian cells is less clear, and evidence so far suggests that it has a role in chromatin compaction and heterochromatin silencing. In this study, we found that the bulk of H2A.Z is excluded from constitutive heterochromatin in differentiated human and mouse cells. Consistent with this observation, analyses of H2A.Z-or H2A-containing mononucleosomes show that the H3 associated with H2A.Z has lower levels of K9 methylation but higher levels of K4 methylation than those associated with H2A. We also found that a fraction of mammalian H2A.Z is monoubiquitylated and that, on the inactive X chromosomes of female cells, the majority of this histone variant is modified by ubiquitin. Finally, ubiquitylation of H2A.Z is mediated by the RING1b E3 ligase of the human polycomb complex, further supporting a silencing role of ubiquitylated H2A.Z. These new findings suggest that mammalian H2A.Z is associated with both euchromatin and facultative heterochromatin and that monoubiquitylation is a specific mark that distinguishes the H2A.Z associated with these different chromatin states.

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

“…4B). We also note the enrichment of MNase-specific LiDs in H2A.Z, in line with the localization of H2A.Z in euchromatin or facultative heterochromatin 29 and its role in transcription elongation. 30,31 We find little or no enrichment in H3K4me1, H3K4me2, H3K4me3, H3K9ac, H3K36me3 or CTCF (Fig.…”

Reconciling the positive and negative roles of histone H2A.Z in gene transcription

“…[27][28][29][30] To date, H2A.Z has been reported to be acetylated, ubiquitylated and sumoylated, but little is known about the functional role of these post-translational modifications. As such, ubiquitylated H2A.Z is found predominantly on the inactive X chromosome, 31 which suggests that this mark is involved in the maintenance or formation of heterochromatin. In Schizosaccharomyces pombe, an acetylated form of H2A.Z regulates chromosome architecture.…”

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

“…[23][24][25] Having so many different locations for a histone variant is very intriguing. Here, we review recent work suggesting that multiple routes can be used to incorporate H2A.Z in the genome and propose that this may lead to different functions for the histone variant.…”