Dissecting the brown adipogenic regulatory network using integrative genomics.
Brown adipocytes regulate energy expenditure via mitochondrial uncoupling, which makes them attractive therapeutic targets to tackle obesity. However, the regulatory mechanisms underlying brown adipogenesis are still poorly understood. To address this, we profiled the transcriptome and chromatin state during mouse brown fat cell differentiation, revealing extensive gene expression changes and chromatin remodeling, especially during the first day post-differentiation. To identify putatively causal regulators, we performed transcription factor binding site overrepresentation analyses in active chromatin regions and prioritized factors based on their expression correlation with the bona-fide brown adipogenic marker Ucp1 across multiple mouse and human datasets. Using loss-of-function assays, we evaluated both the phenotypic effect as well as the transcriptomic impact of several putative regulators on the differentiation process, uncovering ZFP467, HOXA4 and Nuclear Factor I A (NFIA) as novel transcriptional regulators. Of these, NFIA emerged as the regulator yielding the strongest molecular and cellular phenotypes. To examine its regulatory function, we profiled the genomic localization of NFIA, identifying it as a key early regulator of terminal brown fat cell differentiation.
Institute of Bioengineering, École Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland.|Swiss Institute of Bioinformatics, CH-1015 Lausanne, Switzerland.
Rachana N
RN
Pradhan
Institute of Bioengineering, École Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland.|Swiss Institute of Bioinformatics, CH-1015 Lausanne, Switzerland.
Johannes J
JJ
Bues
Institute of Bioengineering, École Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland.|Swiss Institute of Bioinformatics, CH-1015 Lausanne, Switzerland.
Vincent
V
Gardeux
Institute of Bioengineering, École Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland.|Swiss Institute of Bioinformatics, CH-1015 Lausanne, Switzerland.
Petra C
PC
Schwalie
Institute of Bioengineering, École Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland.|Swiss Institute of Bioinformatics, CH-1015 Lausanne, Switzerland.
Daniel
D
Alpern
Institute of Bioengineering, École Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland.|Swiss Institute of Bioinformatics, CH-1015 Lausanne, Switzerland.
Wanze
W
Chen
Institute of Bioengineering, École Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland.|Swiss Institute of Bioinformatics, CH-1015 Lausanne, Switzerland.
Julie
J
Russeil
ILS Bhubhaneshwar, Orissa, India.
Sunil K
SK
Raghav
Institute of Bioengineering, École Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland.|Swiss Institute of Bioinformatics, CH-1015 Lausanne, Switzerland.
Bart
B
Deplancke
D052437:Adipocytes, Brown / Q000378:metabolism*; D050156:Adipogenesis / Q000235:genetics; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D042002:Chromatin Assembly and Disassembly / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D004734:Energy Metabolism / Q000235:genetics*; D005786:Gene Expression Regulation / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D023281:Genomics; D018398:Homeodomain Proteins; D006801:Humans; D051379:Mice; D051839:NFI Transcription Factors / Q000235:genetics*; D014157:Transcription Factors; D059467:Transcriptome / Q000235:genetics; D000071256:Uncoupling Protein 1 / Q000235:genetics*
D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; C484111:Hoxa4 protein, mouse; D051839:NFI Transcription Factors; C497646:Nfia protein, mouse; D014157:Transcription Factors; C000604372:Ucp1 protein, mouse; D000071256:Uncoupling Protein 1; C572221:zinc finger protein 467, mouse