title: Dynamic partnership between TFIIH, PGC-1α and SIRT1 is impaired in trichothiodystrophy.
abstract: The expression of protein-coding genes requires the selective role of many transcription factors, whose coordinated actions remain poorly understood. To further grasp the molecular mechanisms that govern transcription, we focused our attention on the general transcription factor TFIIH, which gives rise, once mutated, to Trichothiodystrophy (TTD), a rare autosomal premature-ageing disease causing inter alia, metabolic dysfunctions. Since this syndrome could be connected to transcriptional defects, we investigated the ability of a TTD mouse model to cope with food deprivation, knowing that energy homeostasis during fasting involves an accurate regulation of the gluconeogenic genes in the liver. Abnormal amounts of gluconeogenic enzymes were thus observed in TTD hepatic parenchyma, which was related to the dysregulation of the corresponding genes. Strikingly, such gene expression defects resulted from the inability of PGC1-α to fulfill its role of coactivator. Indeed, extensive molecular analyses unveiled that wild-type TFIIH cooperated in an ATP-dependent manner with PGC1-α as well as with the deacetylase SIRT1, thereby contributing to the PGC1-α deacetylation by SIRT1. Such dynamic partnership was, however, impaired when TFIIH was mutated, having as a consequence the disruption of PGC1-α recruitment to the promoter of target genes. Therefore, besides a better understanding of the etiology of TFIIH-related disease, our results shed light on the synergistic relationship that exist between different types of transcription factors, which is necessary to properly regulate the expression of protein coding genes.
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, Strasbourg, France.
authors.forename: Hussein
authors.initials: H
authors.lastname: Traboulsi
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, Strasbourg, France.
authors.forename: Serena
authors.initials: S
authors.lastname: Davoli
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, Strasbourg, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Catez
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, Strasbourg, France.
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Egly
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, Strasbourg, France.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Compe
mesh_terms: D000818:Animals; D004260:DNA Repair / Q000235:genetics; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051379:Mice; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D056564:Sirtuin 1 / Q000096:biosynthesis / Q000235:genetics*; D051758:Transcription Factor TFIIH / Q000096:biosynthesis / Q000235:genetics*; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics*; D014158:Transcription, Genetic; D054463:Trichothiodystrophy Syndromes / Q000235:genetics* / Q000473:pathology
chemical_list: D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D014157:Transcription Factors; D051758:Transcription Factor TFIIH; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1