Multivalent binding of PWWP2A to H2A.Z regulates mitosis and neural crest differentiation

Abstract

Replacement of canonical histones with specialized histone variants promotes altering of chromatin structure and function. The essential histone variant H2A.Z affects various DNA‐based processes via poorly understood mechanisms. Here, we determine the comprehensive interactome of H2A.Z and identify PWWP2A as a novel H2A.Z‐nucleosome binder. PWWP2A is a functionally uncharacterized, vertebrate‐specific protein that binds very tightly to chromatin through a concerted multivalent binding mode. Two internal protein regions mediate H2A.Z‐specificity and nucleosome interaction, whereas the PWWP domain exhibits direct DNA binding. Genome‐wide mapping reveals that PWWP2A binds selectively to H2A.Z‐containing nucleosomes with strong preference for promoters of highly transcribed genes. In human cells, its depletion affects gene expression and impairs proliferation via a mitotic delay. While PWWP2A does not influence H2A.Z occupancy, the C‐terminal tail of H2A.Z is one important mediator to recruit PWWP2A to chromatin. Knockdown of PWWP2A in Xenopus results in severe cranial facial defects, arising from neural crest cell differentiation and migration problems. Thus, PWWP2A is a novel H2A.Z‐specific multivalent chromatin binder providing a surprising link between H2A.Z, chromosome segregation, and organ development. image PWWP2A, a novel multivalent H2A.Z‐nucleosome binder, regulates mitotic progression in human cells and cranial facial morphogenesis during frog development, thereby providing a possible link between H2A.Z, chromosome segregation and organ development. Histone H2A.Z interactome analyses identify PWWP2A as novel H2A.Z‐nucleosome binder. Distinct regions in PWWP2A mediate nucleosome binding, H2A.Z specificity, and direct DNA interaction. PWWP2A localizes to H2A.Z‐containing nucleosomes at transcriptional start sites of highly transcribed genes. Depletion of PWWP2A in human cells results in changed gene expression profiles and severe mitotic defects without affecting H2A.Z occupancy. PWWP2A loss during frog development affects proper neural crest stem cell differentiation and migration, causing severe cranial‐facial defects.