title: The KDM5 family is required for activation of pro-proliferative cell cycle genes during adipocyte differentiation.
abstract: The KDM5 family of histone demethylases removes the H3K4 tri-methylation (H3K4me3) mark frequently found at promoter regions of actively transcribed genes and is therefore generally considered to contribute to corepression. In this study, we show that knockdown (KD) of all expressed members of the KDM5 family in white and brown preadipocytes leads to deregulated gene expression and blocks differentiation to mature adipocytes. KDM5 KD leads to a considerable increase in H3K4me3 at promoter regions; however, these changes in H3K4me3 have a limited effect on gene expression per se. By contrast, genome-wide analyses demonstrate that KDM5A is strongly enriched at KDM5-activated promoters, which generally have high levels of H3K4me3 and are associated with highly expressed genes. We show that KDM5-activated genes include a large set of cell cycle regulators and that the KDM5s are necessary for mitotic clonal expansion in 3T3-L1 cells, indicating that KDM5 KD may interfere with differentiation in part by impairing proliferation. Notably, the demethylase activity of KDM5A is required for activation of at least a subset of pro-proliferative cell cycle genes. In conclusion, the KDM5 family acts as dual modulators of gene expression in preadipocytes and is required for early stage differentiation and activation of pro-proliferative cell cycle genes.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark.
authors.forename: Ann-Sofie B
authors.initials: AB
authors.lastname: Brier
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark.
authors.forename: Anne
authors.initials: A
authors.lastname: Loft
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark.|The Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, 2200 Copenhagen N, Denmark.
authors.forename: Jesper G S
authors.initials: JGS
authors.lastname: Madsen
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark.
authors.forename: Thomas
authors.initials: T
authors.lastname: Rosengren
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark.
authors.forename: Ronni
authors.initials: R
authors.lastname: Nielsen
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark.
authors.forename: Søren F
authors.initials: SF
authors.lastname: Schmidt
authors.affiliation: Department of Pathology, Yale School of Medicine, New Haven, CT, USA.
authors.forename: Zongzhi
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Pathology, Yale School of Medicine, New Haven, CT, USA.
authors.forename: Qin
authors.initials: Q
authors.lastname: Yan
authors.affiliation: Equipe Labellisée Ligue Contre le Cancer, Department of Functional Genomics and Cancer, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, UMR7104, Institut National de la Santé et de la Recherche Médicale, U964, Université de Strasbourg, Illkirch, France.
authors.forename: Hinrich
authors.initials: H
authors.lastname: Gronemeyer
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark.
authors.forename: Susanne
authors.initials: S
authors.lastname: Mandrup
mesh_terms: D017667:Adipocytes / Q000166:cytology* / Q000378:metabolism*; D050156:Adipogenesis / Q000235:genetics; D000818:Animals; D002453:Cell Cycle / Q000235:genetics*; D002454:Cell Differentiation / Q000235:genetics*; D002460:Cell Line; D049109:Cell Proliferation; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D056466:Histone Demethylases / Q000235:genetics* / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D005810:Multigene Family; D011401:Promoter Regions, Genetic; D011485:Protein Binding
chemical_list: D006657:Histones; D056466:Histone Demethylases