Project description:Genetic variation governs protein expression through both transcriptional and post-transcriptional processes. To investigate this relationship, we combined a multiplexed, mass spectrometry-based method for protein quantification with an emerging mouse model harboring extensive genetic variation from 8 founder strains. We collected genome-wide mRNA and protein profiling measurements to link genetic variation to protein expression differences in livers from 192 diversity outcross mice. We observed nearly 3,700 protein-level quantitative trait loci (pQTL) with an equal proportion of proteins regulated directly by their cognate mRNA as uncoupled from their transcript. Our analysis reveals an extensive array of at least five models for genetic variant control of protein abundance including direct protein-to-protein associations that act to achieve stoichiometric balance of functionally related enzymes and subunits of multimeric complexes.
Project description:Deletion of the glycerol channel aquaporin-9 (Aqp9) reduces postprandial blood glucose levels in leptin receptor deficient (db/db) obese mice on a C57BL/6×C57BLKS mixed genetic background. Furthermore, shRNA mediated reduction of Aqp9 expression reduces liver triacylglycerol (TAG) accumulation in a diet induced rat model of obesity. The aim of this study was to investigate metabolic effects of Aqp9 deletion in coisogenic db/db mice of the C57BL/6 background. Aqp9wt db/db and Aqp9-/- db/db mice did not differ in body weight and liver TAG contents. On the C57BL/6 genetic background we observed elevated plasma glucose in Aqp9-/- db/db mice (+ 1.1 mM, life-time average) while plasma insulin concentration was reduced at time of death. Glucose levels changed similarly in pentobarbital anesthetized, glucagon challenged Aqp9wt db/db and Aqp9-/- db/db mice. Liver transcriptional profiling did not detect differential gene expression between genotypes. Metabolite profiling revealed a sex independent increase in plasma glycerol (+55%), glucose (+24%) and reduction in threonate (all at q<0.1) in Aqp9-/- db/db mice compared to controls. Metabolite profiling thus confirms a role of AQP9 in glycerol metabolism of obese C57BL/6 db/db mice. In this animal model of obesity Aqp9 gene deletion elevates plasma glucose and does not alleviate hepatosteatosis.
Project description:Genetic variation governs protein expression through both transcriptional and post-transcriptional processes. To investigate this relationship, we combined a multiplexed, mass spectrometry-based method for protein quantification with an emerging mouse model harboring extensive genetic variation from 8 founder strains. We collected genome-wide mRNA and protein profiling measurements to link genetic variation to protein expression differences in livers from 192 diversity outcross mice. We observed nearly 3,700 protein-level quantitative trait loci (pQTL) with an equal proportion of proteins regulated directly by their cognate mRNA as uncoupled from their transcript. Our analysis reveals an extensive array of at least five models for genetic variant control of protein abundance including direct protein-to-protein associations that act to achieve stoichiometric balance of functionally related enzymes and subunits of multimeric complexes.
Project description:Expression Profiling of a Genetic Animal Model of Depression Reveals Novel Molecular Pathways Underlying Depressive-like Behaviours In this study we have used genome-wide microarray expression profiling of the hippocampus and prefrontal/frontal cortex of Flinders Depression Sensitive (FSL) and control Flinders Depression Resistant (FRL) lines to understand molecular basis for the differences between the two lines. We profiled two independent cohorts of Flinders animals derived from the same colony six months apart, each cohort statistically powered to allow independent as well as combined analysis. Using this approach, we were able to validate using real-time-PCR a core set of gene expression differences that showed statistical significance in each of the temporally distinct cohorts, representing consistently maintained features of the model.