Mat1 Inhibits Peroxisome Proliferator-Activated Receptor γ-Mediated Adipocyte Differentiation

Abstract

Mammalian Cdk7, cyclin H, and Mat1 form the kinase submodule of transcription factor IIH (TFIIH) and have been considered ubiquitously expressed elements of the transcriptional machinery. Here we found that Mat1 and Cdk7 levels are undetectable in adipose tissues in vivo and downregulated during adipogenesis, where activation of peroxisome proliferator-activated receptor γ (PPARγ) acts as a critical differentiation switch. Using both Mat1^−/− mouse embryonic fibroblasts and Cdk7 knockdown approaches, we show that the Cdk7 complex is an inhibitor of adipogenesis and is required for inactivation of PPARγ through the phosphorylation of PPARγ-S112. The results demonstrate that the Cdk7 submodule of TFIIH acts as a physiological roadblock to adipogenesis by inhibiting PPARγ activity. The observation that components of TFIIH are absent from transcriptionally active adipose tissue prompts a reevaluation of the ubiquitous nature of basal transcription factors in mammalian tissues.

SUPPLEMENTAL MATERIAL

Supplemental material for this article may be found at http://mcb.asm.org/ .

ACKNOWLEDGMENTS

We are grateful to V. K. K. Chatterjee for providing the PPRE₃-TK-Luc construct, to Bruce Spiegelman for the pSV-SPORT PPARγ and pSV-SPORT PPARγS112A plasmids, to Laszlo Tora for providing the TAF10 antibody, and to Yuan Zhu and Luis Parada for AdCre and AdGFP constructs. We thank Jenny Bärlund, Outi Kokkonen, Saana Laine, and Sari Räsänen for technical assistance and Susanna Räsänen for excellent animal husbandry. Biomedicum Helsinki Molecular Imaging Unit, Biomedicum Virus Core, Biocentrum Helsinki Systems Biology Initiative (MGC Gene Collection), and Biomedicum Genomics are acknowledged for services. Kari Vaahtomeri, Tea Vallenius, and Thomas Westerling are acknowledged for commenting on the manuscript.

This work was supported by Nylands Nation Foundation, Diabetestutkimussäätiö, Finnish Cultural Foundation, Research and Science Foundation of Farmos, Academy of Finland, EU FP6 Program (ENFIN), Finnish Cancer Organizations, and Sigrid Juselius Foundation. K.H. is a graduate student at Helsinki Biomedical Graduate School.