title: Bhlhe40 Represses PGC-1α Activity on Metabolic Gene Promoters in Myogenic Cells.
abstract: PGC-1α is a transcriptional coactivator promoting oxidative metabolism in many tissues. Its expression in skeletal muscle (SKM) is induced by hypoxia and reactive oxidative species (ROS) generated during exercise, suggesting that PGC-1α might mediate the cross talk between oxidative metabolism and cellular responses to hypoxia and ROS. Here we found that PGC-1α directly interacted with Bhlhe40, a basic helix-loop-helix (bHLH) transcriptional repressor induced by hypoxia, and protects SKM from ROS damage, and they cooccupied PGC-1α-targeted gene promoters/enhancers, which in turn repressed PGC-1α transactivational activity. Bhlhe40 repressed PGC-1α activity through recruiting histone deacetylases (HDACs) and preventing the relief of PGC-1α intramolecular repression caused by its own intrinsic suppressor domain. Knockdown of Bhlhe40 mRNA increased levels of ROS, fatty acid oxidation, mitochondrial DNA, and expression of PGC-1α target genes. Similar effects were also observed when the Bhlhe40-mediated repression was rescued by a dominantly active form of the PGC-1α-interacting domain (PID) from Bhlhe40. We further found that Bhlhe40-mediated repression can be largely relieved by exercise, in which its recruitment to PGC-1α-targeted cis elements was significantly reduced. These observations suggest that Bhlhe40 is a novel regulator of PGC-1α activity repressing oxidative metabolism gene expression and mitochondrion biogenesis in sedentary SKM.
authors.affiliation: Department of Life Sciences, National Central University, Jhongli, Taiwan.
authors.forename: Shih Ying
authors.initials: SY
authors.lastname: Chung
authors.affiliation: Department of Life Sciences, National Central University, Jhongli, Taiwan.
authors.forename: Chien Han
authors.initials: CH
authors.lastname: Kao
authors.affiliation: Departament de Bioquímica i Biologia Molecular, Institut de Biomedicina de la Universitat de Barcelona, and CIBER Fisiopatología de la Obesidad y Nutrición, Barcelona, Spain.
authors.forename: Francesc
authors.initials: F
authors.lastname: Villarroya
authors.affiliation: Department of Life Sciences, National Central University, Jhongli, Taiwan.
authors.forename: Hsin Yu
authors.initials: HY
authors.lastname: Chang
authors.affiliation: Department of Life Sciences, National Central University, Jhongli, Taiwan.
authors.forename: Hsuan Chia
authors.initials: HC
authors.lastname: Chang
authors.affiliation: Department of Life Sciences, National Central University, Jhongli, Taiwan.
authors.forename: Sheng Pin
authors.initials: SP
authors.lastname: Hsiao
authors.affiliation: Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Taiwan.
authors.forename: Gunn-Guang
authors.initials: GG
authors.lastname: Liou
authors.affiliation: Department of Life Sciences, National Central University, Jhongli, Taiwan slchen@cc.ncu.edu.tw.
authors.forename: Shen Liang
authors.initials: SL
authors.lastname: Chen
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D002460:Cell Line; D005227:Fatty Acids / Q000378:metabolism; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006655:Histone Deacetylases / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D008813:Mice, Inbred ICR; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism*; D032446:Myoblasts / Q000378:metabolism; D010084:Oxidation-Reduction; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011485:Protein Binding; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017386:Sequence Homology, Amino Acid; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D005227:Fatty Acids; D006655:Histone Deacetylases; D018398:Homeodomain Proteins; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D017382:Reactive Oxygen Species; D014157:Transcription Factors; C491539:Bhlhe40 protein, mouse; C485290:Ppargc1a protein, mouse