title: Histone demethylases KDM4B and KDM6B promotes osteogenic differentiation of human MSCs.
abstract: Human bone marrow mesenchymal stem/stromal cells (MSCs) are multipotent progenitor cells with multilineage differentiation potentials including osteogenesis and adipogenesis. While significant progress has been made in understanding transcriptional controls of MSC fate, little is known about how MSC differentiation is epigenetically regulated. Here we show that the histone demethylases KDM4B and KDM6B play critical roles in osteogenic commitment of MSCs by removing H3K9me3 and H3K27me3. Depletion of KDM4B or KDM6B significantly reduced osteogenic differentiation and increased adipogenic differentiation. Mechanistically, while KDM6B controlled HOX expression by removing H3K27me3, KDM4B promoted DLX expression by removing H3K9me3. Importantly, H3K27me3- and H3K9me3-positive MSCs of bone marrow were significantly elevated in ovariectomized and aging mice in which adipogenesis was highly active. Since histone demethylases are chemically modifiable, KDM4B and KDM6B may present as therapeutic targets for controlling MSC fate choices and lead to clues for new treatment in metabolic bone diseases such as osteoporosis.
authors: State Key Laboratory of Oral Disease and Department of Endodontics, West China School of Stomatology, Sichuan University; Chengdu, Sichuan 610041, China.
authors: Ling
authors: L
authors: Ye
authors: Zhipeng
authors: Z
authors: Fan
authors: Bo
authors: B
authors: Yu
authors: Jia
authors: J
authors: Chang
authors: Khalid
authors: K
authors: Al Hezaimi
authors: Xuedong
authors: X
authors: Zhou
authors: No-Hee
authors: NH
authors: Park
authors: Cun-Yu
authors: CY
authors: Wang
mesh_terms: D017667:Adipocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001853:Bone Marrow / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D055396:Bone Morphogenetic Protein 2 / Q000494:pharmacology; D055415:Bone Morphogenetic Protein 4 / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D019070:Cell Lineage / Q000187:drug effects; D004790:Enzyme Induction / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D006657:Histones / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000378:metabolism*; D008239:Lysine / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*; D051379:Mice; D010012:Osteogenesis / Q000187:drug effects; D010024:Osteoporosis / Q000201:enzymology / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D051785:Smad Proteins / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D055396:Bone Morphogenetic Protein 2; D055415:Bone Morphogenetic Protein 4; D006657:Histones; D018398:Homeodomain Proteins; D051785:Smad Proteins; D014157:Transcription Factors; D056484:Jumonji Domain-Containing Histone Demethylases; C523637:KDM4B protein, human; C524220:KDM6B protein, human; D008239:Lysine