Histone variant H2A.Z deposition and acetylation directs the canonical Notch signaling response

Abstract

A fundamental as yet incompletely understood feature of Notch signal transduction is a transcriptional shift from repression to activation that depends on chromatin regulation mediated by transcription factor RBP-J and associated cofactors. Incorporation of histone variants alter the functional properties of chromatin and are implicated in the regulation of gene expression. Here, we show that depletion of histone variant H2A.Z leads to upregulation of canonical Notch target genes and that the H2A.Z-chaperone TRRAP/p400/Tip60 complex physically associates with RBP-J at Notch-dependent enhancers. When targeted to RBP-J-bound enhancers, the acetyltransferase Tip60 acetylates H2A.Z and upregulates Notch target gene expression. Importantly, the Drosophila homologs of Tip60, p400 and H2A.Z modulate Notch signaling response and growth in vivo. Together, our data reveal that loading and acetylation of H2A.Z are required to assure tight control of canonical Notch activation.

H2A.Z is dispensable for both basal and activated transcription in post-mitotic mouse muscles

“…In cycling MEFs, H2A.Z was depleted in less than two days after adeno-Cre infection and many genes were up and down regulated ( Fig. 1F and data not shown) according to the literature 25,36,37 . We next sought to avoid a possible influence of the cell cycle on gene expression in the absence of H2A.Z.…”

“…H2A.Z dKO cells did not survive more than 9 days after H2A.Z withdrawal, recapitulating the essential function of H2A.Z 26 . We then used RT-qPCR to evaluate the expression of a set of genes known to be affected by the absence of H2A.Z in mouse cells 25 . As expected, they were misregulated in the absence of H2A.Z (Fig.…”

“…H2A.Z is also preferentially bound to other regulatory elements such as enhancers and CTCF-binding sites, which mark insulator sites in the genome 15,17,24 and more generally in chromatin regions where histones have a high turnover. From all these observations, a consensus emerged stipulating that H2A.Z was a key player in the control of transcription 17,18,25 . However, the available data on the link between H2A.Z-containing nucleosomes and transcription remain mainly correlative and based on studies carried out in cultured cells.…”

Ubiquitylated H2A.Z nucleosomes are associated with nuclear architectural proteins and global transcriptional silencing

“…acetylation vs. mono-ubiquitylation, 20). For example, H2A.Z is acetylated at multiple lysines at its N-terminus by the NuA4 complex in S. cerevisiae or Tip60 in Drosophila and mammals (21,22,23,24).…”

“…acetylation vs. mono-ubiquitylation, Draker and Cheung, 2009). H2A.Z is acetylated at multiple lysines at its N-terminus by the NuA4 complex in S. cerevisiae or Tip60 in Drosophila and mammals (Keogh et al, 2006, Millar et al, 2006, Kusch et al, 2004, Giaimo et al, 2018. H2A.Z acetylation directly correlates with transcriptional activation (Millar et al, 2006) and expression of mutant H2A.Z that cannot be acetylated disrupts expression of the master regulator MyoD and downstream differentiation in myoblast cells (Law and Cheung, 2015).…”