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Cell Rep. 2013 Jan 31;3(1):92-102. doi: 10.1016/j.celrep.2012.12.009. Epub 2013 Jan 10.

Chd5 requires PHD-mediated histone 3 binding for tumor suppression.

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1
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.

Abstract

Chromodomain Helicase DNA binding protein 5 (CHD5) is a tumor suppressor mapping to 1p36, a genomic region that is frequently deleted in human cancer. Although CHD5 belongs to the CHD family of chromatin-remodeling proteins, whether its tumor-suppressive role involves an interaction with chromatin is unknown. Here we report that Chd5 binds the unmodified N terminus of H3 through its tandem plant homeodomains (PHDs). Genome-wide chromatin immunoprecipitation studies reveal preferential binding of Chd5 to loci lacking the active mark H3K4me3 and also identify Chd5 targets implicated in cancer. Chd5 mutations that abrogate H3 binding are unable to inhibit proliferation or transcriptionally modulate target genes, which leads to tumorigenesis in vivo. Unlike wild-type Chd5, Chd5-PHD mutants are unable to induce differentiation or efficiently suppress the growth of human neuroblastoma in vivo. Our work defines Chd5 as an N-terminally unmodified H3-binding protein and provides functional evidence that this interaction orchestrates chromatin-mediated transcriptional programs critical for tumor suppression.

PMID:
23318260
PMCID:
PMC3575599
DOI:
10.1016/j.celrep.2012.12.009
[Indexed for MEDLINE]
Free PMC Article
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