title: S6K1 Phosphorylation of H2B Mediates EZH2 Trimethylation of H3: A Determinant of Early Adipogenesis.
abstract: S6K1 has been implicated in a number of key metabolic responses, which contribute to obesity. Critical among these is the control of a transcriptional program required for the commitment of mesenchymal stem cells to the adipocytic lineage. However, in contrast to its role in the cytosol, the functions and targets of nuclear S6K1 are unknown. Here, we show that adipogenic stimuli trigger nuclear translocation of S6K1, leading to H2BS36 phosphorylation and recruitment of EZH2 to H3, which mediates H3K27 trimethylation. This blocks Wnt gene expression, inducing the upregulation of PPARγ and Cebpa and driving increased adipogenesis. Consistent with this finding, white adipose tissue from S6K1-deficient mice exhibits no detectable H2BS36 phosphorylation or H3K27 trimethylation, whereas both responses are highly elevated in obese humans or in mice fed a high-fat diet. These findings define an S6K1-dependent mechanism in early adipogenesis, contributing to the promotion of obesity.
authors.affiliation: Research Center for Epigenome Regulation, School of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea.
authors.forename: Sang Ah
authors.initials: SA
authors.lastname: Yi
authors.affiliation: Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon 16419, Republic of Korea; Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Samsung Medical Center, Seoul 06351, Republic of Korea.
authors.forename: Sung Hee
authors.initials: SH
authors.lastname: Um
authors.affiliation: Division of Cardiology, Department of Medicine, Stanford University School of Medicine, 265 Campus Drive, Room G1120B, Stanford, CA 94305-5454, USA.
authors.forename: Jaecheol
authors.initials: J
authors.lastname: Lee
authors.affiliation: Research Center for Epigenome Regulation, School of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea.
authors.forename: Ji Hee
authors.initials: JH
authors.lastname: Yoo
authors.affiliation: Research Center for Epigenome Regulation, School of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea.
authors.forename: So Young
authors.initials: SY
authors.lastname: Bang
authors.affiliation: Research Center for Epigenome Regulation, School of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea.
authors.forename: Eun Kyung
authors.initials: EK
authors.lastname: Park
authors.affiliation: Research Center for Epigenome Regulation, School of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea.
authors.forename: Min Gyu
authors.initials: MG
authors.lastname: Lee
authors.affiliation: Research Center for Epigenome Regulation, School of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea.
authors.forename: Ki Hong
authors.initials: KH
authors.lastname: Nam
authors.affiliation: Research Center for Epigenome Regulation, School of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea.
authors.forename: Ye Ji
authors.initials: YJ
authors.lastname: Jeon
authors.affiliation: Research Center for Epigenome Regulation, School of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea.
authors.forename: Jong Woo
authors.initials: JW
authors.lastname: Park
authors.affiliation: Department of Biochemistry, School of Medicine, Konkuk University, Seoul 05029, Republic of Korea.
authors.forename: Jueng Soo
authors.initials: JS
authors.lastname: You
authors.affiliation: Research Center for Cell Fate Control, College of Pharmacy, Sookmyung Women's University, Seoul 04310, Republic of Korea.
authors.forename: Sang-Jin
authors.initials: SJ
authors.lastname: Lee
authors.affiliation: Research Center for Cell Fate Control, College of Pharmacy, Sookmyung Women's University, Seoul 04310, Republic of Korea.
authors.forename: Gyu-Un
authors.initials: GU
authors.lastname: Bae
authors.affiliation: Department of Plastic Surgery, College of Medicine, Catholic University of Korea, Seoul 06591, Republic of Korea.
authors.forename: Jong Won
authors.initials: JW
authors.lastname: Rhie
authors.affiliation: Division of Hematology and Oncology, Department of Internal Medicine, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA; Laboratory of Cancer Metabolism, Catalan Institute of Oncology (ICO), Bellvitge Biomedical Research Institute, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), 08908 Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Sara C
authors.initials: SC
authors.lastname: Kozma
authors.affiliation: Division of Hematology and Oncology, Department of Internal Medicine, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA; Laboratory of Cancer Metabolism, Catalan Institute of Oncology (ICO), Bellvitge Biomedical Research Institute, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), 08908 Hospitalet de Llobregat, Barcelona, Spain; Unitat de Bioquímica, Dep. Ciències Fisiològiques II, Facultat de Medicina, Campus Universitari de Bellvitge - IDIBELL, Universitat de Barcelona, 08908 L'Hospitalet de Llobregat, Catalunya, Barcelona, Spain. Electronic address: gthomas@idibell.cat.
authors.forename: George
authors.initials: G
authors.lastname: Thomas
authors.affiliation: Research Center for Epigenome Regulation, School of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea. Electronic address: jhhan551@skku.edu.
authors.forename: Jeung-Whan
authors.initials: JW
authors.lastname: Han
mesh_terms: D017667:Adipocytes / Q000201:enzymology*; D050156:Adipogenesis; D000273:Adipose Tissue / Q000201:enzymology* / Q000473:pathology; D050154:Adiposity; D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D000071221:Enhancer of Zeste Homolog 2 Protein / Q000235:genetics / Q000378:metabolism*; D044127:Epigenesis, Genetic; D006367:HeLa Cells; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D008745:Methylation; D051379:Mice; D009765:Obesity / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000235:genetics / Q000378:metabolism*; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism; D060449:Wnt Signaling Pathway
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; C515848:CEBPA protein, human; C530718:CEBPA protein, mouse; D006657:Histones; D047495:PPAR gamma; D051153:Wnt Proteins; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; C498410:Ezh2 protein, mouse; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C512964:Rps6ka1 protein, mouse; C448901:ribosomal protein S6 kinase, 70kD, polypeptide 1