Structural basis of nucleosome dynamics modulation by histone variants H2A.B and H2AZ2.2

Nucleosomes are dynamic entities with wide-ranging compositional variations. Human histone variants H2A.B and H2A.Z.2.2 play critical roles in multiple biological processes by forming unstable nucleosomes and open chromatin structures, but how H2A.B and H2A.Z.2.2 confer these dynamic features to nucleosomes remains unclear. Here, we report cryo-EMstructures of nucleosome core particles containing human H2A.B (H2A.B-NCP) at atomic resolution, identifying large-scale structural rearrangements in the histone octamer in H2A.B-NCP. H2A.B-NCPcompacts approximately 103 bp ofDNAwrapping around the core histones in approximately 1.2 left-handed superhelical turns, in sharp contrast to canonical nucleosome encompassing approximately 1.7 turns ofDNA. Micrococcal nuclease digestion assay reveals that nineteen H2A.B-specific residues, including aROF(regulating-octamer-folding) sequence of six consecutive residues, are responsible for loosening of H2A.B-NCPs. Unlike H2A.B-NCP, the H2A.Z.2.2-containing nucleosome (Z.2.2-NCP) adopts a less-extended structure and compacts around 125 bp ofDNA. Further investigation uncovers a crucial role for the H2A.Z.2.2-specificROFin both H2A.Z.2.2-NCPopening andSWR1-dependent histone replacement. Taken together, these first high-resolution structure of unstable nucleosomes induced by histone H2A variants elucidate specific functions of H2A.B and H2A.Z.2.2 in enhancing chromatin dynamics.

Automated summary

The study explores the specific functions of human histone variants H2A.B and H2A.Z.2.2 in enhancing chromatin dynamics by investigating the structural rearrangements in nucleosome core particles containing these variants. The results reveal how these variants induce unstable nucleosomes and open chromatin structures, shedding light on their critical roles in various biological processes.