title: Histone H3 lysine 36 methyltransferase Whsc1 promotes the association of Runx2 and p300 in the activation of bone-related genes.
abstract: The orchestration of histone modifiers is required to establish the epigenomic status that regulates gene expression during development. Whsc1 (Wolf-Hirschhorn Syndrome candidate 1), a histone H3 lysine 36 (H3K36) trimethyltransferase, is one of the major genes associated with Wolf-Hirshhorn syndrome, which is characterized by skeletal abnormalities. However, the role of Whsc1 in skeletal development remains unclear. Here, we show that Whsc1 regulates gene expression through Runt-related transcription factor (Runx) 2, a transcription factor central to bone development, and p300, a histone acetyltransferase, to promote bone differentiation. Whsc1-/- embryos exhibited defects in ossification in the occipital bone and sternum. Whsc1 knockdown in pre-osteoblast cells perturbed histone modification patterns in bone-related genes and led to defects in bone differentiation. Whsc1 increased the association of p300 with Runx2, activating the bone-related genes Osteopontin (Opn) and Collagen type Ia (Col1a1), and Whsc1 suppressed the overactivation of these genes via H3K36 trimethylation. Our results suggest that Whsc1 fine-tunes the expression of bone-related genes by acting as a modulator in balancing H3K36 trimethylation and histone acetylation. Our results provide novel insight into the mechanisms by which this histone methyltransferase regulates gene expression.
authors.affiliation: Division of Gene Therapy Science, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Yu Fei
authors.initials: YF
authors.lastname: Lee
authors.affiliation: Division of Gene Therapy Science, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Nimura
authors.affiliation: Division of Gene Therapy Science, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Wan Ning
authors.initials: WN
authors.lastname: Lo
authors.affiliation: Division of Gene Therapy Science, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Kotaro
authors.initials: K
authors.lastname: Saga
authors.affiliation: Division of Gene Therapy Science, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Yasufumi
authors.initials: Y
authors.lastname: Kaneda
mesh_terms: D000818:Animals; D001842:Bone and Bones / Q000378:metabolism*; D002460:Cell Line; D050659:Core Binding Factor Alpha 1 Subunit / Q000378:metabolism*; D050676:Core Binding Factor Alpha 2 Subunit / Q000378:metabolism; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000378:metabolism*; D008239:Lysine / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D050880:p300-CBP Transcription Factors / Q000378:metabolism*; D000099224:p300-CBP-Associated Factor
chemical_list: D050659:Core Binding Factor Alpha 1 Subunit; D050676:Core Binding Factor Alpha 2 Subunit; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; D006657:Histones; D008239:Lysine; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C543213:WHSC1 protein, mouse