H2A.Z: a molecular rheostat for transcriptional control

Abstract

The replacement of nucleosomal H2A with the histone variant H2A.Z is critical for regulating DNA-mediated processes across eukaryotes and for early development of multicellular organisms. How this variant performs these seemingly diverse roles has remained largely enigmatic. Here, we discuss recent mechanistic insights that have begun to reveal how H2A.Z functions as a molecular rheostat for gene control. We focus on specific examples in metazoans as a model for understanding how H2A.Z integrates information from histone post-translational modifications, other histone variants, and transcription factors (TFs) to regulate proper induction of gene expression programs in response to cellular cues. Finally, we propose a general model of how H2A.Z incorporation regulates chromatin states in diverse processes.

Figure 1.. H2A.Z nucleosome composition at promoters influences nucleosome stability and transcriptional state

(Top) The transition from homotypic to heterotypic H2A.Z nucleosomes can regulate gene activation through regulation of transcription elongation. (Bottom) H2A.Z nucleosomes can impact the stability of the +1 nucleosome and RNA polymerase II progression.

Figure 2.. H2A.Z regulates gene induction

(A) In response to androgen receptor (AR) signaling, H2A.Z allows binding of AR to its response elements, at both promoters and enhancers, and along with acH4 recruits Brd2 and RNA polymerase II to mediate gene activation. (B) H2A.Z is enriched at both active and silent, poised genes in embryonic stem cells. The effect of H2A.Z on transcription depends on the balance of both activating and repressive histone post-translational modifications as well as H2A.Z-specific deposition and removal complexes in response to cellular cues.

Figure 3.. H2A.Z acts a scaffold for binding of chromatin remodelers and pioneer transcription factors

During endodermal differentiation, the pioneer transcription factor Foxa2 binds to H2A.Z nucleosomes, leading to the recruitment of chromatin remodelers, nucleosome depletion, transcription factor binding, and subsequent gene activation.