Bivalent recognition of nucleosomes by the tandem PHD fingers of the CHD4 ATPase is required for CHD4-mediated repression.
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 for their association with chromatin. We found that PHD1/2 targets nucleosomes in a multivalent manner, concomitantly engaging two histone H3 tails. This robust synergistic interaction displaces HP1γ from pericentric sites, inducing changes in chromatin structure and leading to the dispersion of the heterochromatic mark H3K9me3. 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.
Department of Pharmacology, University of Colorado Denver School of Medicine, Aurora, CO 80045, USA.
Catherine A
CA
Musselman
Julita
J
Ramírez
Jennifer K
JK
Sims
Robyn E
RE
Mansfield
Samuel S
SS
Oliver
John M
JM
Denu
Joel P
JP
Mackay
Paul A
PA
Wade
James
J
Hagman
Tatiana G
TG
Kutateladze
D000595:Amino Acid Sequence; D057809:HEK293 Cells; D006570:Heterochromatin / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D018398:Homeodomain Proteins / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009707:Nucleosomes / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D012097:Repressor Proteins / Q000378:metabolism*; D014158:Transcription, Genetic
D006570:Heterochromatin; D006657:Histones; D018398:Homeodomain Proteins; D009707:Nucleosomes; D012097:Repressor Proteins; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex