Highlights d Systematic method to combine mouse liver network and human lipid GWAS for discovery d Identification of a conserved liver cholesterol module across mouse populations d Prioritization of genes replicated in mouse and associated with human lipid traits d Validation of Sestrin1 as a gene that regulates cholesterol biosynthesis
Purpose of review More than one hundred loci have been identified from human genome-wide association studies (GWAS) for blood lipids. Despite the success of GWAS in identifying loci, subsequent prioritization of causal genes related to these loci remains a challenge. To address this challenge, recent work suggests that candidate causal genes within loci can be prioritized through cross-species integration using genome-wide data from the mouse. Recent findings Mouse model systems provide unparalleled access to primary tissues, like the liver, that are not readily available for human studies. Given the key role the liver plays in controlling blood lipid levels and the wealth of liver genome-wide transcript and protein data available in the mouse, these data can be leveraged. Using coexpression network analysis approaches with mouse genome-wide data, coupled with cross-species analysis of human lipid GWAS, causal genes within lipid loci can be prioritized. Prioritization through both mouse and human along with biochemical validation provide a systematic and valuable method to discover lipid metabolism genes. Summary The prioritization of causal lipid genes within GWAS loci is a challenging process requiring a multidisciplinary approach. Integration of data types across species, such as the mouse, can aid in causal gene prioritization.
Chronic kidney disease (CKD) involves disturbances in iron metabolism including anemia caused by insufficient erythropoietin (EPO) production. However, underlying mechanisms responsible for the dysregulation of cellular iron metabolism are incompletely defined. Using the unilateral ureteral obstruction (UUO) model in Irp1+/+ and Irp1-/- mice we asked if iron regulatory proteins (IRP), the central regulators of cellular iron metabolism and also suppressors of EPO production, contribute to the etiology of anemia in kidney failure. We identified a significant reduction in IRP protein level and RNA binding activity that associated with a loss of the iron uptake protein transferrin receptor 1, increased expression of the iron storage protein subunits H- and L-ferritin, and a low but overall variable level of stainable iron in the obstructed kidney. This reduction in IRP RNA binding activity and ferritin RNA levels suggests the concomitant rise in ferritin expression and iron content in kidney failure is IRP-dependent. In contrast, the reduction in Epo mRNA level in the obstructed kidney was not rescued by genetic ablation of IRP1 suggesting disruption of normal HIF-2a regulation. Furthermore, reduced expression of some HIFa target genes in UUO occurred in the face of increased expression of HIFa proteins and the prolyl hydroxylases (PHD) 2 and PHD1, the latter of which is not known to be HIFa mediated. Our results suggest that the IRP system drives changes in cellular iron metabolism that are associated with kidney failure in UUO but that the impact of IRP on EPO production is overridden by disrupted hypoxia signaling.
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