S6K1 Phosphorylation of H2B Mediates EZH2 Trimethylation of H3: A Determinant of Early Adipogenesis

Sang Ah Yi; Sung Hee Um; Jaecheol Lee; Ji Hee Yoo; So Young Bang; Eun Kyung Park; Min Gyu Lee; Ki Hong Nam; Ye Ji Jeon; Jong Woo Park; Jueng Soo You; Sang-Jin Lee; Gyu-Un Bae; Jong Won Rhie; Sara C Kozma; George Thomas; Jeung-Whan Han

doi:10.1016/j.molcel.2016.03.011

S6K1 Phosphorylation of H2B Mediates EZH2 Trimethylation of H3: A Determinant of Early Adipogenesis

Mol Cell. 2016 May 5;62(3):443-452. doi: 10.1016/j.molcel.2016.03.011. Epub 2016 Apr 14.

Authors

Sang Ah Yi¹, Sung Hee Um², Jaecheol Lee³, Ji Hee Yoo¹, So Young Bang¹, Eun Kyung Park¹, Min Gyu Lee¹, Ki Hong Nam¹, Ye Ji Jeon¹, Jong Woo Park¹, Jueng Soo You⁴, Sang-Jin Lee⁵, Gyu-Un Bae⁵, Jong Won Rhie⁶, Sara C Kozma⁷, George Thomas⁸, Jeung-Whan Han⁹

Affiliations

¹ Research Center for Epigenome Regulation, School of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea.
² 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.
³ Division of Cardiology, Department of Medicine, Stanford University School of Medicine, 265 Campus Drive, Room G1120B, Stanford, CA 94305-5454, USA.
⁴ Department of Biochemistry, School of Medicine, Konkuk University, Seoul 05029, Republic of Korea.
⁵ Research Center for Cell Fate Control, College of Pharmacy, Sookmyung Women's University, Seoul 04310, Republic of Korea.
⁶ Department of Plastic Surgery, College of Medicine, Catholic University of Korea, Seoul 06591, Republic of Korea.
⁷ 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.
⁸ 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.
⁹ Research Center for Epigenome Regulation, School of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea. Electronic address: jhhan551@skku.edu.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adipocytes / enzymology*
Adipogenesis*
Adipose Tissue / enzymology*
Adipose Tissue / pathology
Adiposity
Animals
CCAAT-Enhancer-Binding Proteins / metabolism
Disease Models, Animal
Enhancer of Zeste Homolog 2 Protein / genetics
Enhancer of Zeste Homolog 2 Protein / metabolism*
Epigenesis, Genetic
HeLa Cells
Histones / genetics
Histones / metabolism*
Humans
Male
Methylation
Mice
Obesity / enzymology*
Obesity / genetics
Obesity / pathology
PPAR gamma / genetics
PPAR gamma / metabolism
Phosphorylation
Protein Processing, Post-Translational*
Ribosomal Protein S6 Kinases, 70-kDa / genetics
Ribosomal Protein S6 Kinases, 70-kDa / metabolism*
Ribosomal Protein S6 Kinases, 90-kDa / genetics
Ribosomal Protein S6 Kinases, 90-kDa / metabolism*
Transcription, Genetic
Transfection
Wnt Proteins / genetics
Wnt Proteins / metabolism
Wnt Signaling Pathway

Substances

CCAAT-Enhancer-Binding Proteins
CEBPA protein, human
CEBPA protein, mouse
Histones
PPAR gamma
Wnt Proteins
EZH2 protein, human
Enhancer of Zeste Homolog 2 Protein
Ezh2 protein, mouse
Ribosomal Protein S6 Kinases, 70-kDa
Ribosomal Protein S6 Kinases, 90-kDa
Rps6ka1 protein, mouse
ribosomal protein S6 kinase, 70kD, polypeptide 1

Grants and funding

R01 CA158768/CA/NCI NIH HHS/United States