title: Chd5 requires PHD-mediated histone 3 binding for tumor suppression.
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.
authors: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
authors: Shilpi
authors: S
authors: Paul
authors: Alex
authors: A
authors: Kuo
authors: Thomas
authors: T
authors: Schalch
authors: Hannes
authors: H
authors: Vogel
authors: Leemor
authors: L
authors: Joshua-Tor
authors: W Richard
authors: WR
authors: McCombie
authors: Or
authors: O
authors: Gozani
authors: Molly
authors: M
authors: Hammell
authors: Alea A
authors: AA
authors: Mills
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000473:pathology; D004265:DNA Helicases / Q000737:chemistry* / Q000378:metabolism*; D056426:Genetic Loci / Q000235:genetics; D016678:Genome / Q000235:genetics; D006657:Histones / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D008239:Lysine / Q000378:metabolism; D008745:Methylation; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009447:Neuroblastoma / Q000235:genetics / Q000473:pathology; D010455:Peptides / Q000378:metabolism; D011485:Protein Binding; D013329:Structure-Activity Relationship
chemical_list: D006657:Histones; D018398:Homeodomain Proteins; D010455:Peptides; D004265:DNA Helicases; C550983:Chd6 protein, mouse; D008239:Lysine