Project description:The homeodomain transcription factor Prep1 was previously shown to regulate insulin sensitivity. Our aim was to study the specific role of Prep1 for the regulation of energy metabolism in skeletal muscle. Muscle specific ablation of Prep1 resulted in increased expression of respiratory chain subunits. This finding was consistent with an increase in mitochondrial enzyme activity without affecting mitochondrial volume fraction as assessed by electron microscopy. Metabolic phenotyping revealed no differences in daily energy expenditure or body composition. However, during treadmill exercise challenge, Prep1 ablation resulted in a higher maximal oxidative capacity and better endurance. Elevated PGC-1α expression was identified as a cause for increased mitochondrial capacity in Prep1-ablated mice. Prep1 stabilizes p160 Mybbp1a, a known inhibitor of PGC-1α activity. Thereby, P160 protein levels were significantly lower in muscle of Prep1-ablated mice. By a ChIPseq approach, PREP1-binding sites in genes encoding mitochondrial components (e.g. Ndufs2) were identified that might be responsible for elevated OXPHOS proteins in the muscle of Prep1 nullmutants. These results suggest that Prep1 exhibits additional direct effects on regulation of mitochondrial proteins. We therefore conclude that Prep1 is a regulator of oxidative phosphorylation components via direct and indirect mechanisms.
Project description:The homeodomain transcription factor Prep1 was previously shown to regulate insulin sensitivity. Our aim was to study the specific role of Prep1 for the regulation of energy metabolism in skeletal muscle. Muscle specific ablation of Prep1 resulted in increased expression of respiratory chain subunits. This finding was consistent with an increase in mitochondrial enzyme activity without affecting mitochondrial volume fraction as assessed by electron microscopy. Metabolic phenotyping revealed no differences in daily energy expenditure or body composition. However, during treadmill exercise challenge, Prep1 ablation resulted in a higher maximal oxidative capacity and better endurance. Elevated PGC-1α expression was identified as a cause for increased mitochondrial capacity in Prep1-ablated mice. Prep1 stabilizes p160 Mybbp1a, a known inhibitor of PGC-1α activity. Thereby, P160 protein levels were significantly lower in muscle of Prep1-ablated mice. By a ChIPseq approach, PREP1-binding sites in genes encoding mitochondrial components (e.g. Ndufs2) were identified that might be responsible for elevated OXPHOS proteins in the muscle of Prep1 nullmutants. These results suggest that Prep1 exhibits additional direct effects on regulation of mitochondrial proteins. We therefore conclude that Prep1 is a regulator of oxidative phosphorylation components via direct and indirect mechanisms. Consequence of Prep1 ablation in skeletal muscle was investigated in Prep1deltaSM mice and compared to Prep1 flox mice, both on C57BL/6 background. 4 mice of each genotype were used to extract RNA from the tibialis anterior muscle.
Project description:We collected whole genome testis expression data from hybrid zone mice. We integrated GWAS mapping of testis expression traits and low testis weight to gain insight into the genetic basis of hybrid male sterility.
Project description:We collected whole genome testis expression data from hybrid zone mice. We integrated GWAS mapping of testis expression traits and low testis weight to gain insight into the genetic basis of hybrid male sterility. Gene expression was measured in whole testis from males aged 62-86 days. Samples include 190 first generation lab-bred male offspring of wild-caught mice from the Mus musculus musculus - M. m. domesticus hybrid zone.
Project description:To characterize the genetic basis of hybrid male sterility in detail, we used a systems genetics approach, integrating mapping of gene expression traits with sterility phenotypes and QTL. We measured genome-wide testis expression in 305 male F2s from a cross between wild-derived inbred strains of M. musculus musculus and M. m. domesticus. We identified several thousand cis- and trans-acting QTL contributing to expression variation (eQTL). Many trans eQTL cluster into eleven ‘hotspots,’ seven of which co-localize with QTL for sterility phenotypes identified in the cross. The number and clustering of trans eQTL - but not cis eQTL - were substantially lower when mapping was restricted to a ‘fertile’ subset of mice, providing evidence that trans eQTL hotspots are related to sterility. Functional annotation of transcripts with eQTL provides insights into the biological processes disrupted by sterility loci and guides prioritization of candidate genes. Using a conditional mapping approach, we identified eQTL dependent on interactions between loci, revealing a complex system of epistasis. Our results illuminate established patterns, including the role of the X chromosome in hybrid sterility.