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 underlying mechanisms by which it acts are not completely understood. Recently, we identified the zinc finger protein ZNF512B as an H2A.Z-, HMG20A- and PWWP2A-associated protein. Here, we report that ZNF512B binds 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 assays we demonstrate that this internal NIM is both necessary and sufficient for robust 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. Surprisingly, high levels of ZNF512B expression lead to nuclear protein and chromatin aggregation foci that form independent of the interaction with the NuRD complex but depend on the zinc finger domains of ZNF512B. Our study has implications for diseases in which ZNF512B expression is deregulated, such as cancer and neurodegenerative diseases, and hint at the existence of more proteins as potential NuRD interactors.