Project description:The goal of this project is to understand the dosage-dependent effects of SIRT1, the most conserved mammalian NAD+-dependent protein deacetylase, on cell proliferation and metabolism. Our recent studies indicate that SIRT1 has a dosage-dependent effect on cell metabolism and proliferation. Heterozygous deletion of SIRT1 enhance glycolysis and glutaminolysis, thereby promoting cell proliferation and stress resistance. Yet homozygous deletion of SIRT1 triggers cellular apoptotic pathways, leading to increased cell death. To understand the molecular mechanisms underlying this dose-dependent effect, we examined the transcriptomes of SIRT1 WT, Het, and KO MEFs cultured in complete DMEM medium by microarray analysis.
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.
