title: Epigenetic Control of the Bone-master Runx2 Gene during Osteoblast-lineage Commitment by the Histone Demethylase JARID1B/KDM5B.
abstract: Transcription factor Runx2 controls bone development and osteoblast differentiation by regulating expression of a significant number of bone-related target genes. Here, we report that transcriptional activation and repression of the Runx2 gene via its osteoblast-specific P1 promoter (encoding mRNA for the Runx2/p57 isoform) is accompanied by selective deposition and elimination of histone marks during differentiation of mesenchymal cells to the osteogenic and myoblastic lineages. These epigenetic profiles are mediated by key components of the Trithorax/COMPASS-like and Polycomb group complexes together with histone arginine methylases like PRMT5 and lysine demethylases like JARID1B/KDM5B. Importantly, knockdown of the H3K4me2/3 demethylase JARID1B, but not of the demethylases UTX and NO66, prevents repression of the Runx2 P1 promoter during myogenic differentiation of mesenchymal cells. The epigenetically forced expression of Runx2/p57 and osteocalcin, a classical bone-related target gene, under myoblastic-differentiation is accompanied by enrichment of the H3K4me3 and H3K27ac marks at the Runx2 P1 promoter region. Our results identify JARID1B as a key component of a potent epigenetic switch that controls mesenchymal cell fate into myogenic and osteogenic lineages.
authors.affiliation: Center for Biomedical Research, Faculty of Biological Sciences and Faculty of Medicine, Universidad Andres Bello, Santiago, 8370146, Chile; Faculty of Sciences, Universidad de Chile, Santiago, 7800003, Chile; FONDAP Center for Genome Regulation, Santiago, Chile.
authors.forename: Adriana
authors.initials: A
authors.lastname: Rojas
authors.affiliation: Center for Biomedical Research, Faculty of Biological Sciences and Faculty of Medicine, Universidad Andres Bello, Santiago, 8370146, Chile; FONDAP Center for Genome Regulation, Santiago, Chile.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Aguilar
authors.affiliation: Center for Biomedical Research, Faculty of Biological Sciences and Faculty of Medicine, Universidad Andres Bello, Santiago, 8370146, Chile.
authors.forename: Berta
authors.initials: B
authors.lastname: Henriquez
authors.affiliation: University of Vermont Medical School, Burlington, Vermont 05405.
authors.forename: Jane B
authors.initials: JB
authors.lastname: Lian
authors.affiliation: University of Vermont Medical School, Burlington, Vermont 05405.
authors.forename: Janet L
authors.initials: JL
authors.lastname: Stein
authors.affiliation: University of Vermont Medical School, Burlington, Vermont 05405.
authors.forename: Gary S
authors.initials: GS
authors.lastname: Stein
authors.affiliation: Mayo Clinic, Rochester, Minnesota 55905.
authors.forename: Andre J
authors.initials: AJ
authors.lastname: van Wijnen
authors.affiliation: Center for Biomedical Research, Faculty of Biological Sciences and Faculty of Medicine, Universidad Andres Bello, Santiago, 8370146, Chile.
authors.forename: Brigitte
authors.initials: B
authors.lastname: van Zundert
authors.affiliation: Faculty of Sciences, Universidad de Chile, Santiago, 7800003, Chile; FONDAP Center for Genome Regulation, Santiago, Chile.
authors.forename: Miguel L
authors.initials: ML
authors.lastname: Allende
authors.affiliation: Center for Biomedical Research, Faculty of Biological Sciences and Faculty of Medicine, Universidad Andres Bello, Santiago, 8370146, Chile; FONDAP Center for Genome Regulation, Santiago, Chile. Electronic address: mmontecino@unab.cl.
authors.forename: Martin
authors.initials: M
authors.lastname: Montecino
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D019070:Cell Lineage; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D044127:Epigenesis, Genetic; D006657:Histones / Q000378:metabolism; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000378:metabolism*; D051379:Mice; D010006:Osteoblasts / Q000166:cytology* / Q000378:metabolism; D011401:Promoter Regions, Genetic
chemical_list: D050659:Core Binding Factor Alpha 1 Subunit; D004268:DNA-Binding Proteins; D006657:Histones; C493716:Runx2 protein, mouse; D056484:Jumonji Domain-Containing Histone Demethylases; C485614:Kdm5b protein, mouse
keywords: Runx2; epigenetics; gene expression; histone modification; osteoblast; transcription