Bivalent Recognition of a Single Nucleosome by the Tandem PHD Fingers of CHD4 is Required for CHD4-Mediated Repression

Abstract

CHD4 is a catalytic subunit of the NuRD (nucleosome remodeling and deacetylase) complex essential in transcriptional regulation, chromatin assembly and DNA damage repair. CHD4 contains tandem plant homeodomain (PHD) fingers connected by a short linker, the biological function of which remains unclear. Here we explore the combinatorial action of the CHD4 PHD1/2 fingers and detail the molecular basis of their association with chromatin. We found that the inter-domain organization of PHD1/2 leads to specific targeting of a single nucleosome in a multivalent manner, concomitantly engaging both of the histone H3 tails. This robust synergistic interaction displaces HP1γ from pericentric sites, inducing changes in chromatin structure and dispersion of the heterochromatic marks H3K9me3 and H4K20me3. We demonstrate that recognition of the histone H3 tails by the PHD fingers is required for repressive activity of the CHD4/NuRD complex. Together, our data elucidate the molecular mechanism of multivalent association of the PHD fingers with chromatin and reveal their critical role in the regulation of CHD4 functions.