Recent neurodevelopmental and cognitive studies have described dysregulated expression of immediate early genes (IEGs) as a phenotype and suggest that it may underlie the etiology of increasingly common brain disorders such as Autism and Schizophrenia. Transcription induced by neuronal activity involves the coordinated action of many different processes and factors acting at the membrane, in the cytoplasm, and in the nucleus.

At the chromatin level, one of these factors is the histone variant H2A.Z. While this variant has known roles in memory consolidation and cerebellar development, it has been reported as both a transcriptional activator and repressor. As such, its contribution to transcriptional regulation remains elusive. The work presented here provides evidence supporting distinct roles of H2A.Z hypervariants, H2A.Z.1 and H2A.Z.2, in transcriptional regulation of IEGs and demonstrates a regulatory mechanisms in which the incorporation of H2A.Z.2, not H2A.Z.1, in nucleosomes near the transcription start sites (TSS) of rapid IEGs is required for pausing of RNA Polymerase II (Pol II).

At the cell-signaling level, activity-induced transcription is regulated by multiple calcium-dependent signaling cascades. It has been reported that the Ras/mitogen-activated protein kinase (MAPK) pathway is indispensable for rapid IEG transcription. However, much remains unclear about the involvement of other calcium-dependent signaling cascades in regulating expression of these genes. This study reports evidence supporting the idea that MAPK and Calcineurin (CaN) signaling pathways are both necessary for optimal expression of most rapid IEGs in response to neuronal activity. However, the extent to which each pathway contributes to expression varies from gene to gene.

This study demonstrates variation in the contributions of individual factors (H2A.Z hypervariants) and processes (calcium-induced signaling pathways) to transcriptional regulation. The work herein highlights a need for regulatory mechanisms governing IEG expression to be investigated further at the individual gene level.