BioProject

The Cdk7/cyclin H/ménage-à-trois 1 (MAT1) heterotrimer has proposed functions in transcription as the kinase component of basal transcription factor TFIIH and is activated in adult hearts by hypertrophic pathways. More...

The Cdk7/cyclin H/ménage-à-trois 1 (MAT1) heterotrimer has proposed functions in transcription as the kinase component of basal transcription factor TFIIH and is activated in adult hearts by hypertrophic pathways. Using cardiac-specific Cre, we ablated MAT1 in myocardium. Despite reduced Cdk7 activity, MAT1-deficient hearts grew normally. However, fatal heart failure ensued at 6-8 weeks. By microarray profiling, quantitative RT-PCR, and Western blotting at 4 weeks, genes for energy metabolism were found to be suppressed selectively, including targets of peroxisome proliferator-activated receptor-gamma coactivator-1 (PGC-1). Cardiac metabolic defects were substantiated in isolated perfused hearts and isolated mitochondria. In culture, deleting MAT1 with Cre disrupted PGC-1 function: PGC-1α failed to activate PGC-1-responsive promoters and nuclear receptors, GAL4-PGC-1α was functionally defective, and PGC-1β likewise was deficient. PGC-1 was shown to interact with MAT1 and Cdk7, in co-precipitation assays. Thus, we demonstrate an unforeseen essential role for MAT1 in operation of the PGC-1 family of co-activators. Keywords: conditional knockout in mice Overall design: MAT1F/F mice (Korsisaari et al., 2002) were bred with mice expressing Cre recombinase under the control of the cardiomyocyte-specific α-myosin heavy chain (αMHC) promoter (Gaussin et al., 2002a) and back-bred to MAT1F/F mice to generate the cardiac-specific knockout (αMHC-Cre+/0; MAT1F/F; CKO; Fig. 1A, B). Control mice were αMHC-Cre+/0; MAT1F/+ littermates, differing by the presence of one wild-type MAT1 allele, and excluding Cre-mediated toxicity as a basis for phenotypic disparity. Cardiac RNA samples were analyze at 2 or 4 weeks of age (N = 3-5 for each condition tested. Less...