Fig. 3

Regulation of H2A.Z and its involvement in transcription. Two examples are used to explain the function of H2A.Z in gene regulation: a the case of the androgen system focusing on the PSA locus and b the case of the estrogen system focusing on the TFF1 locus. a In a repressed or poised (OFF) state, the H2A.Z-specific loading machineries are recruited to the PSA locus via not well-defined mechanisms that may involve TFs and/or histone modifications. In this scenario, H2A.Z is deposited by SRCAP and/or p400/Tip60 complexes [119, 122] and the deacetylation and ubiquitination machineries are probably recruited via interactions with DNA binding proteins and/or posttranslationally modified histones (not depicted in the figure). The deacetylation machinery removes the acetylation mark from H2A.Z, which is instead ubiquitinated on its C-terminus by E3 ubiquitin ligases (we speculate that RING1B is involved in the AR signaling cascade [58, 145]). Upon gene activation (ON), deubiquitination (for example, USP10 [51]) and loading/acetylation/deubiquitination machineries are recruited/stabilized via interactions with the Androgen Receptor (AR) that binds to its cognate sequences (androgen receptor-binding element, ARE) and/or histone modifications [119, 122]. This leads to H2A.Z deubiquitination [52] and acetylation [59, 122] finally leading to gene activation which is associated with reduced H2A.Z occupancy [51, 52]. b In a repressed (OFF) state, FoxA1 binds to the distal FoxA1-binding site (FBS) of the TFF1 locus where it recruits the p400/Tip60 complex that supports loading of H2A.Z. In this state, H2A.Z is poorly enriched at the TFF1 promoter and, as consequence, nucleosome occupancy is poorly defined [50]. Upon gene induction, the estrogen receptor α (ERα) binds to its cognate sequence (estrogen receptor-binding element, ERE) where it recruits the p400/Tip60 complex leading to loading of H2A.Z at the promoter and as consequence increased nucleosome positioning and finally to gene activation. At the same time, H2A.Z enrichment at the FBS is reduced [50]