Genetic Variation Determines PPARγ Function and Anti-diabetic Drug Response In Vivo

SNPs affecting disease risk often reside in non-coding genomic regions. Here, we show that SNPs are highly enriched at mouse strain-selective adipose tissue binding sites for PPARγ, a nuclear receptor for anti-diabetic drugs. Many such SNPs alter binding motifs for PPARγ or cooperating factors and functionally regulate nearby genes whose expression is strain selective and imbalanced in heterozygous F1 mice. Moreover, genetically determined binding of PPARγ accounts for mouse strain-specific transcriptional effects of TZD drugs, providing proof of concept for personalized medicine related to nuclear receptor genomic occupancy. In human fat, motif-altering SNPs cause differential PPARγ binding, provide a molecular mechanism for some expression quantitative trait loci, and are risk factors for dysmetabolic traits in genome-wide association studies. One PPARγ motif-altering SNP is associated with HDL levels and other metabolic syndrome parameters. Thus, natural genetic variation in PPARγ genomic occupancy determines individual disease risk and drug response

Unique transcriptional and chromatin profiles of memory CD8+ T cells

Compared to their naïve pre-cursors (TN), memory T cells (TM) can provide superior protection from pathogenic infections, and can cause significant pathology during unwanted immune responses, such as those underlying autoimmune diseases and transplant rejection. Thus, understanding the unique attributes of TM cells should facilitate development of new vaccines and immunoregulatory therapies. One distinguishing property of CD8+TM cells is their ability to rapidly execute effector functions following stimulation; however, the mechanisms underlying this ability are not well-defined. Specifically, little is known about whether or how a unique, stimulation-induced gene expression program contributes to TM cells\u27 accelerated responses. Using whole genome mRNA profiling, we found that following stimulation, in comparison to T N cells, TM more robustly up-regulated a large set of genes that included amino acid metabolic enzymes and transporters, RNA processing factors, and transcription factors involved in cellular activation, showing that more robust transcript induction by TM cells is not limited to those encoding effector molecules In addition to more robust induction of this functionally diverse gene set, TM cells also uniquely induced a gene set involved in regulating nuclear export. In contrast, TN cells uniquely down-regulated factors that can condense chromatin, and we identified the repression of several histone deacetylases as an early event following TN activation, suggesting that changes in chromatin structure mediated by histone acetylation are important to CD8+ T cell differentiation. Based on these results, we developed a novel assay to measure the total, per cell level of di-acetylated histone H3 (diAcH3) in CD8 + T cells using flow cytometry. Interestingly, resting CD8 + TM cells had a higher level of this modification than their TN counterparts, and CD8+ TM primed in the absence of CD4+ T cell help, which are defective in rapid recall ability, had a lower level than TM primed in a CD4+ T cell-sufficient environment. Given the positive correlation of a locus\u27s diAcH3 level with its transcriptional accessibility, these data suggest that in resting TM cells, diAcH3 may help keep loci open and accessible to the transcriptional machinery, particularly those whose expression is important for executing a rapid recall response