title: EZH2 and KDM6A act as an epigenetic switch to regulate mesenchymal stem cell lineage specification.
abstract: The methyltransferase, Enhancer of Zeste homology 2 (EZH2), trimethylates histone 3 lysine 27 (H3K27me3) on chromatin and this repressive mark is removed by lysine demethylase 6A (KDM6A). Loss of these epigenetic modifiers results in developmental defects. We demonstrate that Ezh2 and Kdm6a transcript levels change during differentiation of multipotential human bone marrow-derived mesenchymal stem cells (MSC). Enforced expression of Ezh2 in MSC promoted adipogenic in vitro and inhibited osteogenic differentiation potential in vitro and in vivo, whereas Kdm6a inhibited adipogenesis in vitro and promoted osteogenic differentiation in vitro and in vivo. Inhibition of EZH2 activity and knockdown of Ezh2 gene expression in human MSC resulted in decreased adipogenesis and increased osteogenesis. Conversely, knockdown of Kdm6a gene expression in MSC leads to increased adipogenesis and decreased osteogenesis. Both Ezh2 and Kdm6a were shown to affect expression of master regulatory genes involved in adipogenesis and osteogenesis and H3K27me3 on the promoters of master regulatory genes. These findings demonstrate an important epigenetic switch centered on H3K27me3 which dictates MSC lineage determination.
authors.affiliation: Mesenchymal Stem Cell Laboratory, School of Medical Sciences, Faculty of Health Sciences, South Australia, Australia.
authors.forename: Sarah
authors.initials: S
authors.lastname: Hemming
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Cakouros
authors.forename: Sandra
authors.initials: S
authors.lastname: Isenmann
authors.forename: Lachlan
authors.initials: L
authors.lastname: Cooper
authors.forename: Danijela
authors.initials: D
authors.lastname: Menicanin
authors.forename: Andrew
authors.initials: A
authors.lastname: Zannettino
authors.forename: Stan
authors.initials: S
authors.lastname: Gronthos
mesh_terms: D017667:Adipocytes / Q000166:cytology / Q000378:metabolism; D050156:Adipogenesis / Q000235:genetics; D000293:Adolescent; D000328:Adult; D000818:Animals; D019070:Cell Lineage / Q000235:genetics*; D002478:Cells, Cultured; D000071221:Enhancer of Zeste Homolog 2 Protein; D044127:Epigenesis, Genetic; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D056466:Histone Demethylases / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D008239:Lysine / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism*; D008745:Methylation; D051379:Mice; D016513:Mice, SCID; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism; D010012:Osteogenesis / Q000235:genetics; D063151:Polycomb Repressive Complex 2 / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D014158:Transcription, Genetic; D055815:Young Adult
chemical_list: D006657:Histones; D009687:Nuclear Proteins; D056466:Histone Demethylases; C523998:KDM6A protein, human; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2; D008239:Lysine
keywords: Adipocytes; Chromatin; Epigenetic modifier; Epigenetics; Mesenchymal stem cells; Osteoblasts