Mechanistic basis of gene regulation by SRCAP and H2A.Z

A central problem in gene regulation is to discriminate gene regulatory functions of chromatin composition from the one of chromatin-modifying complexes. This question has been virtually unexplored in the context of the H2A.Z histone variant and its incorporation into nucleosomes by the Snf2 Related CREBBP Activator Protein (SRCAP) complex. Here we combine rapid SRCAP depletion, a SRCAP mutant lacking H2A.Z deposition activity, and quantitative genome-wide approaches to dissect how SRCAP and H2A.Z regulate transcription in pluripotent stem cells. We find that SRCAP exhibits essential H2A.Z-independent functions in preventing DNA binding of lineage-specific transcription factors at enhancers and stimulating transcription factor binding at promoters. In contrast, H2A.Z acts mainly as a transcriptional repressor that requires dynamic reloading by SRCAP throughout the cell cycle. Our study demonstrates how the SRCAP-H2A.Z axis broadly orchestrates transcription to promote self-renewal, inhibit differentiation, and maintain plasticity of pluripotent stem cells.