CFDP1 is required for histone variant H2A.Z deposition by the human SRCAP chromatin remodeling complex

Abstract

Craniofacial Developmental Protein 1 (CFDP1) is a member of the evolutionarily conserved family of Bucentaur (BCNT) proteins and is required for cell survival and differentiation during tooth development. Its yeast homolog is involved in histone variant H2A.Z deposition by the yeast SWR1C remodeler. Direct connections between CFDP1, H2A.Z deposition, and the mammalian SWR1 homolog, Snf2-Related CREBBP Activator Protein (SRCAP), are poorly understood. Here, we perform detailed biochemical reconstitution and characterization of the human SRCAP complex (SRCAP-C). We find that CFDP1 weakly interacts with SRCAP-C in a salt concentration-dependent manner and is essential for H2A.Z dimer exchange by SRCAP-C. We show that CFDP1 stimulates the basal ATPase activity of reconstituted SRCAP-C, suggesting a requirement for CFDP1 in regulating intrinsic catalytic ATPase activity. Additionally, CFDP1 deficiency in human induced pluripotent stem cells (hiPSCs) leads to a genome-wide reduction of H2A.Z, H3K27me3, and H3K4me3 deposition, accompanied by the upregulation of developmental genes normally marked by these modifications. Taken together, our results provide mechanistic insights into how CFDP1 regulates histone variant H2A.Z deposition by SRCAP-C. Given mutations in the SRCAP gene cause Floating-Harbor syndrome, a rare, dominant developmental disorder, our study provides an additional link between craniofacial development and SRCAP-mediated H2A.Z deposition.