title: Comparative Transcriptomic and Epigenomic Analyses Reveal New Regulators of Murine Brown Adipogenesis.
abstract: Increasing energy expenditure through brown adipocyte recruitment is a promising approach to combat obesity. We report here the comprehensive profiling of the epigenome and transcriptome throughout the lineage commitment and differentiation of C3H10T1/2 mesenchymal stem cell line into brown adipocytes. Through direct comparison to datasets from differentiating white adipocytes, we systematically identify stage- and lineage-specific coding genes, lncRNAs and microRNAs. Utilizing chromatin state maps, we also define stage- and lineage-specific enhancers, including super-enhancers, and their associated transcription factor binding motifs and genes. Through these analyses, we found that in brown adipocytes, brown lineage-specific genes are pre-marked by both H3K4me1 and H3K27me3, and the removal of H3K27me3 at the late stage is necessary but not sufficient to promote brown gene expression, while the pre-deposition of H3K4me1 plays an essential role in poising the brown genes for expression in mature brown cells. Moreover, we identify SOX13 as part of a p38 MAPK dependent transcriptional response mediating early brown cell lineage commitment. We also identify and subsequently validate PIM1, SIX1 and RREB1 as novel regulators promoting brown adipogenesis. Finally, we show that SIX1 binds to adipogenic and brown marker genes and interacts with C/EBPα, C/EBPβ and EBF2, suggesting their functional cooperation during adipogenesis.
authors.affiliation: Singapore Institute for Clinical Sciences, Agency for Science, Technology and Research (A*STAR), Singapore, Republic of Singapore.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Brunmeir
authors.affiliation: Center for Stem Cell Biology and Regenerative Medicine, MOE Key Laboratory of Bioinformatics, THU-PKU Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, China.
authors.forename: Jingyi
authors.initials: J
authors.lastname: Wu
authors.affiliation: Singapore Institute for Clinical Sciences, Agency for Science, Technology and Research (A*STAR), Singapore, Republic of Singapore.
authors.forename: Xu
authors.initials: X
authors.lastname: Peng
authors.affiliation: Singapore Institute for Clinical Sciences, Agency for Science, Technology and Research (A*STAR), Singapore, Republic of Singapore.
authors.forename: Sun-Yee
authors.initials: SY
authors.lastname: Kim
authors.affiliation: Singapore Institute for Clinical Sciences, Agency for Science, Technology and Research (A*STAR), Singapore, Republic of Singapore.
authors.forename: Sofi G
authors.initials: SG
authors.lastname: Julien
authors.affiliation: Singapore Institute for Clinical Sciences, Agency for Science, Technology and Research (A*STAR), Singapore, Republic of Singapore.
authors.forename: Qiongyi
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Center for Stem Cell Biology and Regenerative Medicine, MOE Key Laboratory of Bioinformatics, THU-PKU Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Xie
authors.affiliation: Singapore Institute for Clinical Sciences, Agency for Science, Technology and Research (A*STAR), Singapore, Republic of Singapore.|Institute of Molecular and Cell Biology, A*STAR, Singapore, Republic of Singapore.
authors.forename: Feng
authors.identifier: http://orcid.org/0000-0003-2016-7521
authors.initials: F
authors.lastname: Xu
mesh_terms: D050156:Adipogenesis / Q000235:genetics*; D002001:Adipose Tissue, Brown / Q000254:growth & development / Q000378:metabolism; D000818:Animals; D001324:Autoantigens / Q000235:genetics; D051792:Basic Helix-Loop-Helix Proteins / Q000096:biosynthesis / Q000235:genetics*; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D022762:CCAAT-Enhancer-Binding Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics; D019070:Cell Lineage / Q000235:genetics; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D004734:Energy Metabolism / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D059630:Mesenchymal Stem Cells; D051379:Mice; D009765:Obesity / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D062085:RNA, Long Noncoding / Q000096:biosynthesis; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D059467:Transcriptome / Q000235:genetics
chemical_list: D001324:Autoantigens; D051792:Basic Helix-Loop-Helix Proteins; D022782:CCAAT-Enhancer-Binding Protein-beta; D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D062085:RNA, Long Noncoding; D014157:Transcription Factors; C530718:CEBPA protein, mouse; C545013:Cebpb protein, mouse; C489922:Ebf2 protein, mouse; C000606556:Rreb1 protein, mouse; C490947:Six1 protein, mouse; C110455:Sox13 protein, mouse