Histone H2A.Z is essential for estrogen receptor signaling

Abstract

Incorporation of H2A.Z into the chromatin of inactive promoters has been shown to poise genes for their expression. Here we provide strong evidence that H2A.Z is incorporated into the promoter regions of estrogen receptor (ERα) target genes only upon gene induction, and that, in a cyclic pattern. Moreover, members of the human H2A.Z-depositing complex, p400, also follow the same gene recruitment kinetics as H2A.Z. Importantly, cellular depletion of H2A.Z or p400 leads to a severe defect in estrogen signaling, including loss of estrogen-specific cell proliferation. We find that incorporation of H2A.Z within TFF1 promoter chromatin allows nucleosomes to adopt preferential positions along the DNA translational axis. Finally, we provide evidence that H2A.Z is essential to allow estrogen-responsive enhancer function. Taken together, our results provide strong mechanistic insight into how H2A.Z regulates ERα-mediated gene expression and provide a novel link between H2A.Z–p400 and ERα-dependent gene regulation and enhancer function.

Chromatin Remodeling by Imitation Switch (ISWI) Class ATP-dependent Remodelers Is Stimulated by Histone Variant H2A.Z

“…Htz1, the yeast H2A.Z homolog, is shown to flank transcription start sites and is therefore correlated with the same nucleosomes positioned by Isw2 (36 -39). Consistent with H2A.Z nucleosomes also being important in nucleosome positioning in humans, promoter nucleosomes positioned by transcriptional stimulation by ER␣, remain diffuse in the TTF1 promoter upon depletion of H2A.Z (15). Generally, positioning of H2A.Z is observed at transcription start sites in humans mainly at the ϩ1 nucleosome downstream.…”

“…Combined with our observations (Fig. 1) and those of others (7,(12)(13)(14)(15) that other remodelers are enriched on H2A.Z chromatin, this suggests a general role for H2A.Z in specifying increased remodeling.…”

“…Enrichment of a remodeler with H2A.Z might provide one mechanism for increasing remodeling as has been indicated previously (7,15). Additionally, inclusion of H2A.Z in chromatin could effect the proficiency of the remodeling reaction itself.…”

“…In addition to its localization at promoters, H2A.Z is also detected at many loci staged for reorganization in response to stimulation such as at binding sites for the transcription factor glucocorticoid receptor (7), p53 (8), and estrogen receptor ␣ (ER␣) 2 (9). These studies suggest that H2A.Z might play a regulatory role, either by causing a change in chromatin structure or by recruiting chromatin-modifying proteins.…”

“…In humans, H2A.Z is detected at sites of transcriptionally regulated DNase I hypersensitivity; accessibility of DNase I to some of these sites is mediated by the Swi/Snf motor protein BRG1 (7). Furthermore, recruitment of BRG1 to ER␣-induced promoter TTF1 is dependent on H2A.Z deposition (15). Thus, chromatin remodeler associations with H2A.Z have been widely reported; however, direct evidence for H2A.Z specifying chromatin remodeling activity remains to be demonstrated.…”