RT Journal Article SR Electronic T1 Histone Hypervariants H2A.Z.1 and H2A.Z.2 Play Independent and Context-Specific Roles in Neuronal Activity-Induced Transcription of Arc/Arg3.1 and Other Immediate Early Genes JF eneuro JO eNeuro FD Society for Neuroscience SP ENEURO.0040-17.2017 DO 10.1523/ENEURO.0040-17.2017 A1 Carissa J. Dunn A1 Pushpita Sarkar A1 Emma R. Bailey A1 Shannon Farris A1 Meilan Zhao A1 James M. Ward A1 Serena M. Dudek A1 Ramendra N. Saha YR 2017 UL http://www.eneuro.org/content/early/2017/08/17/ENEURO.0040-17.2017.abstract AB The histone variant H2A.Z is an essential and conserved regulator of eukaryotic gene transcription. However, the exact role of this histone in the transcriptional process remains perplexing. In vertebrates, H2A.Z has two hypervariants – H2A.Z.1 and H2A.Z.2 – that have almost identical sequences except for three amino acid residues. Due to such similarity, functional specificity of these hypervariants in neurobiological processes, if any, remain largely unknown. In this study with dissociated rat cortical neurons, we asked if H2A.Z hypervariants have distinct functions in regulating basal and activity-induced gene transcription. Hypervariant-specific RNAi and microarray analyses revealed that H2A.Z.1 and H2A.Z.2 regulate basal expression of largely non-overlapping gene-sets, including genes that code for several synaptic proteins. In response to neuronal activity, rapid transcription of our model gene Arc is impaired by depletion of H2A.Z.2, but not H2A.Z.1. This impairment is partially rescued by co-depletion of the H2A.Z chaperone, ANP32E. In contrast, under a different context (after 48 hours of TTX), rapid transcription of Arc is impaired by depletion of either hypervariant. Such context-dependent roles of H2A.Z hypervariants, as revealed by our multiplexed gene expression assays, are also evident with several other immediate early genes, where regulatory roles of these hypervariants vary from gene to gene under different conditions. Together, our data suggest that H2A.Z hypervariants have context-specific roles that complement each other to mediate activity-induced neuronal gene transcription.Significance Statement Epigenetic regulation of activity-induced gene transcription is pivotal in mediating neuronal responses that underlie several transcription-dependent downstream brain processes, yet it remains poorly understood. Thus, understanding roles of such epigenetic processes and their core components, such as variant histone H2A.Z, is necessary to comprehend brain development and function. In vertebrates, H2A.Z has two hypervariants, H2A.Z.1 and H2A.Z.2, which are encoded by different genes and differ by only three amino acids. Despite such similar sequences, we provide evidence suggesting that they regulate non-overlapping gene cohorts in neurons and play context-specific, non-redundant roles in activity-induced transcription of immediate early genes. Together, our findings represent a substantial departure from the current H2A.Z biology by shifting the focus to independent contributions of H2A.Z hypervariants.