title: The FBXL10/KDM2B scaffolding protein associates with novel polycomb repressive complex-1 to regulate adipogenesis.
abstract: Polycomb repressive complex 1 (PRC1) plays an essential role in the epigenetic repression of gene expression during development and cellular differentiation via multiple effector mechanisms, including ubiquitination of H2A and chromatin compaction. However, whether it regulates the stepwise progression of adipogenesis is unknown. Here, we show that FBXL10/KDM2B is an anti-adipogenic factor that is up-regulated during the early phase of 3T3-L1 preadipocyte differentiation and in adipose tissue in a diet-induced model of obesity. Interestingly, inhibition of adipogenesis does not require the JmjC demethylase domain of FBXL10, but it does require the F-box and leucine-rich repeat domains, which we show recruit a noncanonical polycomb repressive complex 1 (PRC1) containing RING1B, SKP1, PCGF1, and BCOR. Knockdown of either RING1B or SKP1 prevented FBXL10-mediated repression of 3T3-L1 preadipocyte differentiation indicating that PRC1 formation mediates the inhibitory effect of FBXL10 on adipogenesis. Using ChIP-seq, we show that FBXL10 recruits RING1B to key specific genomic loci surrounding the key cell cycle and the adipogenic genes Cdk1, Uhrf1, Pparg1, and Pparg2 to repress adipogenesis. These results suggest that FBXL10 represses adipogenesis by targeting a noncanonical PRC1 complex to repress key genes (e.g. Pparg) that control conversion of pluripotent cells into the adipogenic lineage.
authors.affiliation: From the Division of Metabolic Medicine, the Translational Systems Biology and Medicine Initiative Center for Disease Biology and Integrative Medicine, University of Tokyo, Tokyo 153-8904, Japan, inagaki@lsbm.org.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Inagaki
authors.affiliation: From the Division of Metabolic Medicine.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Iwasaki
authors.affiliation: From the Division of Metabolic Medicine.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Matsumura
authors.affiliation: the Translational Systems Biology and Medicine Initiative Center for Disease Biology and Integrative Medicine, University of Tokyo, Tokyo 153-8904, Japan, Laboratory for Systems Biology and Medicine.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kawamura
authors.affiliation: From the Division of Metabolic Medicine, the Translational Systems Biology and Medicine Initiative Center for Disease Biology and Integrative Medicine, University of Tokyo, Tokyo 153-8904, Japan, Laboratory for Systems Biology and Medicine.
authors.forename: Toshiya
authors.initials: T
authors.lastname: Tanaka
authors.affiliation: From the Division of Metabolic Medicine.
authors.forename: Yohei
authors.initials: Y
authors.lastname: Abe
authors.affiliation: From the Division of Metabolic Medicine.
authors.forename: Ayumu
authors.initials: A
authors.lastname: Yamasaki
authors.affiliation: From the Division of Metabolic Medicine.
authors.forename: Yuya
authors.initials: Y
authors.lastname: Tsurutani
authors.affiliation: From the Division of Metabolic Medicine, the Laboratory of Genome and Biosignals, Tokyo University of Pharmacy and Life Science, Tokyo 192-0392, Japan.
authors.forename: Ayano
authors.initials: A
authors.lastname: Yoshida
authors.affiliation: the Translational Systems Biology and Medicine Initiative Center for Disease Biology and Integrative Medicine, University of Tokyo, Tokyo 153-8904, Japan, Laboratory for Systems Biology and Medicine.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Chikaoka
authors.affiliation: From the Division of Metabolic Medicine, the Laboratory of Genome and Biosignals, Tokyo University of Pharmacy and Life Science, Tokyo 192-0392, Japan.
authors.forename: Kanako
authors.initials: K
authors.lastname: Nakamura
authors.affiliation: From the Division of Metabolic Medicine, the Translational Systems Biology and Medicine Initiative Center for Disease Biology and Integrative Medicine, University of Tokyo, Tokyo 153-8904, Japan.
authors.forename: Kenta
authors.initials: K
authors.lastname: Magoori
authors.affiliation: Genome Science Division, Research Center for Advanced Science and Technology, University of Tokyo, Tokyo 153-8904, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Nakaki
authors.affiliation: the Metabolic Disease Program, Sanford-Burnham Medical Research Institute, Orlando, Florida 32827, and.
authors.forename: Timothy F
authors.initials: TF
authors.lastname: Osborne
authors.affiliation: the Laboratory of Genome and Biosignals, Tokyo University of Pharmacy and Life Science, Tokyo 192-0392, Japan.
authors.forename: Kiyoko
authors.initials: K
authors.lastname: Fukami
authors.affiliation: the Translational Systems Biology and Medicine Initiative Center for Disease Biology and Integrative Medicine, University of Tokyo, Tokyo 153-8904, Japan, Genome Science Division, Research Center for Advanced Science and Technology, University of Tokyo, Tokyo 153-8904, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Aburatani
authors.affiliation: Laboratory for Systems Biology and Medicine.
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Kodama
authors.affiliation: From the Division of Metabolic Medicine, the Translational Systems Biology and Medicine Initiative Center for Disease Biology and Integrative Medicine, University of Tokyo, Tokyo 153-8904, Japan, jmsakai-tky@umin.ac.jp.
authors.forename: Juro
authors.initials: J
authors.lastname: Sakai
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000166:cytology / Q000378:metabolism*; D050156:Adipogenesis / Q000502:physiology*; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation; D047369:Chromatin Immunoprecipitation; D044783:F-Box Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020869:Gene Expression Profiling; D006657:Histones / Q000378:metabolism; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D056484:Jumonji Domain-Containing Histone Demethylases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000090263:Leucine-Rich Repeat Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D020411:Oligonucleotide Array Sequence Analysis; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D063150:Polycomb Repressive Complex 1 / Q000235:genetics / Q000378:metabolism*; D020033:Protein Isoforms; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D054875:Ubiquitination
chemical_list: D015415:Biomarkers; D018797:Cell Cycle Proteins; D044783:F-Box Proteins; D006657:Histones; D000090263:Leucine-Rich Repeat Proteins; D047495:PPAR gamma; D020033:Protein Isoforms; D011506:Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D056484:Jumonji Domain-Containing Histone Demethylases; C524747:Kdm2b protein, mouse; D063150:Polycomb Repressive Complex 1
keywords: 3T3-L1 cells; Adipocyte; Adipogenesis; Cell Differentiation; FBXL10/KDM2B/JHDM1B; Mitotic Clonal Expansion (MCE); Peroxisome Proliferator-activated Receptor (PPAR); Polycomb; Polycomb Repressive Complex 1 (PRC1); RING1B