title: The transcription factor SOX6 contributes to the developmental origins of obesity by promoting adipogenesis.
abstract: An association between impaired fetal growth and the postnatal development of obesity has been established. Here, by comparing adipocytes differentiated from mesenchymal stem cells (MSCs) taken from the umbilical cord and derived from normal and growth-restricted neonates, we identified the transcription factor SOX6 as highly expressed only in growth-restricted individuals. We found that SOX6 regulates adipogenesis in vertebrate species by activating adipogenic regulators including PPARγ, C/EBPα and MEST. We further show that SOX6 interacts with β-catenin in adipocytes, suggesting an inhibition of WNT/β-catenin signaling, thereby promoting adipogenesis. The upstream regulatory region of the MEST gene in MSCs from growth-restricted subjects harbors hypomethylated CpGs next to SOX6 binding motifs, and we found that SOX6 binding is impaired by adjacent CpG methylation. In summary, we report that SOX6 is a novel regulator of adipogenesis synergizing with epigenetic mechanisms.
authors.affiliation: Singapore Institute for Clinical Sciences (SICS), Agency for Science Technology and Research (A*STAR), 30 Medical Drive, Singapore, Singapore 117609.
authors.forename: Shi Chi
authors.initials: SC
authors.lastname: Leow
authors.affiliation: Genome Institute of Singapore, Agency for Science Technology and Research (A*STAR), Singapore, Singapore 138672.
authors.forename: Jeremie
authors.initials: J
authors.lastname: Poschmann
authors.affiliation: Singapore Institute for Clinical Sciences (SICS), Agency for Science Technology and Research (A*STAR), 30 Medical Drive, Singapore, Singapore 117609.
authors.forename: Peh Gek
authors.initials: PG
authors.lastname: Too
authors.affiliation: Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore 636921.
authors.forename: Juan
authors.initials: J
authors.lastname: Yin
authors.affiliation: Singapore Institute for Clinical Sciences (SICS), Agency for Science Technology and Research (A*STAR), 30 Medical Drive, Singapore, Singapore 117609.
authors.forename: Roy
authors.initials: R
authors.lastname: Joseph
authors.affiliation: Singapore Institute for Clinical Sciences (SICS), Agency for Science Technology and Research (A*STAR), 30 Medical Drive, Singapore, Singapore 117609.
authors.forename: Craig
authors.initials: C
authors.lastname: McFarlane
authors.affiliation: Singapore Institute for Clinical Sciences (SICS), Agency for Science Technology and Research (A*STAR), 30 Medical Drive, Singapore, Singapore 117609.
authors.forename: Shaillay
authors.initials: S
authors.lastname: Dogra
authors.affiliation: Department of Surgery, National University Hospital, National University of Singapore, Singapore 119074.
authors.forename: Asim
authors.initials: A
authors.lastname: Shabbir
authors.affiliation: Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore 636921 Developmental and Biomedical Genetics Laboratory, Institute of Molecular and Cell Biology, Agency for Science Technology and Research (A*STAR), Singapore, Singapore 138673.
authors.forename: Philip W
authors.initials: PW
authors.lastname: Ingham
authors.affiliation: Genome Institute of Singapore, Agency for Science Technology and Research (A*STAR), Singapore, Singapore 138672.
authors.forename: Shyam
authors.initials: S
authors.lastname: Prabhakar
authors.affiliation: Singapore Institute for Clinical Sciences (SICS), Agency for Science Technology and Research (A*STAR), 30 Medical Drive, Singapore, Singapore 117609 Department of Endocrinology, Tan Tock Seng Hospital, Singapore, Singapore 308433.
authors.forename: Melvin K S
authors.initials: MK
authors.lastname: Leow
authors.affiliation: Singapore Institute for Clinical Sciences (SICS), Agency for Science Technology and Research (A*STAR), 30 Medical Drive, Singapore, Singapore 117609 Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228.
authors.forename: Yung Seng
authors.initials: YS
authors.lastname: Lee
authors.affiliation: Department of Obstetrics and Gynaecology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228.
authors.forename: Kai Lyn
authors.initials: KL
authors.lastname: Ng
authors.affiliation: Singapore Institute for Clinical Sciences (SICS), Agency for Science Technology and Research (A*STAR), 30 Medical Drive, Singapore, Singapore 117609 Department of Obstetrics and Gynaecology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228.
authors.forename: Yap Seng
authors.initials: YS
authors.lastname: Chong
authors.affiliation: Singapore Institute for Clinical Sciences (SICS), Agency for Science Technology and Research (A*STAR), 30 Medical Drive, Singapore, Singapore 117609 Liggins Institute, University of Auckland, Auckland 1142, New Zealand.
authors.forename: Peter D
authors.initials: PD
authors.lastname: Gluckman
authors.affiliation: Singapore Institute for Clinical Sciences (SICS), Agency for Science Technology and Research (A*STAR), 30 Medical Drive, Singapore, Singapore 117609 walter_stunkel@sics.a-star.edu.sg.
authors.forename: Walter
authors.initials: W
authors.lastname: Stünkel
mesh_terms: D016475:3T3 Cells; D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism; D050156:Adipogenesis / Q000187:drug effects / Q000235:genetics; D000818:Animals; D001665:Binding Sites; D002454:Cell Differentiation; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics; D015536:Down-Regulation / Q000187:drug effects; D006801:Humans; D007231:Infant, Newborn; D007236:Infant, Small for Gestational Age / Q000378:metabolism; D007814:Larva / Q000187:drug effects; D050356:Lipid Metabolism / Q000235:genetics; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D009765:Obesity / Q000235:genetics*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D011506:Proteins / Q000235:genetics; D055755:SOXD Transcription Factors / Q000378:metabolism*; D014280:Triglycerides / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000187:drug effects / Q000235:genetics; D015027:Zebrafish
chemical_list: D016376:Oligonucleotides, Antisense; D011506:Proteins; D055755:SOXD Transcription Factors; D014280:Triglycerides; C103637:mesoderm specific transcript protein
keywords: Developmental origins; Epigenetics; Fetal growth restriction; Human; Mesenchymal stem cells; Mouse; Obesity; Transcription factor; Zebrafish