ZNF512B binds RBBP4 via a variant NuRD interaction motif and aggregates chromatin in a NuRD complex-independent manner.

Abstract

The evolutionarily conserved histone variant H2A.Z plays a crucial role in various DNA-based processes, but the mechanisms underlying its activity are not completely understood. Recently, we identified the zinc finger (ZF) protein ZNF512B as a protein associated with H2A.Z, HMG20A and PWWP2A. Here, we report that high levels of ZNF512B expression lead to nuclear protein and chromatin aggregation foci that form in a manner that is dependent on the ZF domains of ZNF512B. Notably, we demonstrate ZNF512B binding to the nucleosome remodeling and deacetylase (NuRD) complex. We discover a conserved amino acid sequence within ZNF512B that resembles the NuRD-interaction motif (NIM) previously identified in FOG-1 and other transcriptional regulators. By solving the crystal structure of this motif bound to the NuRD component RBBP4 and by applying several biochemical and biophysical assays, we demonstrate that this internal NIM is both necessary and sufficient for robust and high-affinity NuRD binding. Transcriptome analyses and reporter assays identify ZNF512B as a repressor of gene expression that can act in both NuRD-dependent and -independent ways. Our study might have implications for diseases in which ZNF512B expression is deregulated, such as cancer and neurodegenerative diseases, and hints at the existence of more proteins as potential NuRD interactors.