title: Gcn5 and PCAF regulate PPARγ and Prdm16 expression to facilitate brown adipogenesis.
abstract: The acetyltransferase Gcn5 is critical for embryogenesis and shows partial functional redundancy with its homolog PCAF. However, the tissue- and cell lineage-specific functions of Gcn5 and PCAF are still not well defined. Here we probe the functions of Gcn5 and PCAF in adipogenesis. We found that the double knockout (DKO) of Gcn5/PCAF inhibits expression of the master adipogenic transcription factor gene PPARγ, thereby preventing adipocyte differentiation. The adipogenesis defects in Gcn5/PCAF DKO cells are rescued by ectopic expression of peroxisome proliferator-activated receptor γ (PPARγ), suggesting Gcn5/PCAF act upstream of PPARγ to facilitate adipogenesis. The requirement of Gcn5/PCAF for PPARγ expression was unexpectedly bypassed by prolonged treatment with an adipogenic inducer, 3-isobutyl-1-methylxanthine (IBMX). However, neither PPARγ ectopic expression nor prolonged IBMX treatment rescued defects in Prdm16 expression in DKO cells, indicating that Gcn5/PCAF are essential for normal Prdm16 expression. Gcn5/PCAF regulate PPARγ and Prdm16 expression at different steps in the transcription process, facilitating RNA polymerase II recruitment to Prdm16 and elongation of PPARγ transcripts. Overall, our study reveals that Gcn5/PCAF facilitate adipogenesis through regulation of PPARγ expression and regulate brown adipogenesis by influencing Prdm16 expression.
authors: Department of Molecular Carcinogenesis, Center for Cancer Epigenetics, The University of Texas M. D. Anderson Cancer Center, Smithville, Texas, USA Laboratory of Endocrinology and Receptor Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors: Qihuang
authors: Q
authors: Jin
authors: Laboratory of Endocrinology and Receptor Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors: Chaochen
authors: C
authors: Wang
authors: Department of Molecular Carcinogenesis, Center for Cancer Epigenetics, The University of Texas M. D. Anderson Cancer Center, Smithville, Texas, USA.
authors: Xianghong
authors: X
authors: Kuang
authors: Laboratory of Muscle Stem Cells and Gene Regulation, National Institute of Arthritis, Musculoskeletal, and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors: Xuesong
authors: X
authors: Feng
authors: Laboratory of Muscle Stem Cells and Gene Regulation, National Institute of Arthritis, Musculoskeletal, and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors: Vittorio
authors: V
authors: Sartorelli
authors: Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors: Hao
authors: H
authors: Ying
authors: Laboratory of Endocrinology and Receptor Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA kaig@niddk.nih.gov sroth@mdanderson.org.
authors: Kai
authors: K
authors: Ge
authors: Department of Molecular Carcinogenesis, Center for Cancer Epigenetics, The University of Texas M. D. Anderson Cancer Center, Smithville, Texas, USA kaig@niddk.nih.gov sroth@mdanderson.org.
authors: Sharon Y R
authors: SY
authors: Dent
mesh_terms: D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D052437:Adipocytes, Brown / Q000187:drug effects / Q000378:metabolism*; D050156:Adipogenesis / Q000187:drug effects; D000818:Animals; D020134:Catalytic Domain; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D051379:Mice; D008954:Models, Biological; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D012320:RNA Polymerase III / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D050880:p300-CBP Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D047495:PPAR gamma; D010726:Phosphodiesterase Inhibitors; C521133:Prdm16 protein, mouse; D014157:Transcription Factors; D050880:p300-CBP Transcription Factors; D012320:RNA Polymerase III; D015056:1-Methyl-3-isobutylxanthine