Genetic Variation Determines PPARgamma Function and Antidiabetic Drug Response In Vivo [RNA-seq]

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 PPARgamma, a nuclear receptor for antidiabetic drugs. Many such SNPs alter binding motifs for PPARgamma or cooperating factors, and functionally regulate nearby genes whose expression is strain-selective and imbalanced in heterozygous F1 mice. Moreover, genetically-determined binding of PPARgamma 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 PPARgamma binding, provide a molecular mechanism for some expression quantitative trait loci, and are risk factors for dysmetabolic traits in genome- wide association studies. One PPARgamma motif-altering SNP is associated with HDL levels and other metabolic syndrome parameters. Thus, natural genetic variation in PPARgamma genomic occupancy determines individual disease risk and drug response. Comparison of 5 RNA-seq experiments between 2 strains of mice differing in diet and fat depot. One of the experiments was evaluation of the response to a drug Rosiglitazone. Our RNA-seq data comprises primarily of 4 main experiments: The first experiment consists of samples taken from 2 strains of mice and their F1 progeny The samples are all taken from the same depot and when the mice were fed the same chow diet The second experiment has 2 parts, the first one involves samples taken from the 2 strains from the same eWAT depot when they were kept on a Low Fat Diet (LFD) This first part serves as a control for the second one in which the mice were treated with a drug, rosiglitazone in conjunction with a LFD The third experiment consists of samples taken from mice being fed on LFD. The samples are taken from the eWAT depot for both the strains. The fourth experiment consists of samples taken from mice being fed on LFD. The samples are taken from the iWAT depot for both the strains. We also have a solitary sample from a GRO-seq experiment which was done on eWAT in a B6 strain of mice being fed a LFD eWAT: epididymal White Adipose Tissue iWAT: inguinal White Adipose Tissue LFD-12w: mice were fed a control low fat diet (Research Diet D12450B) chow: mice were fed standard rodent chow Diet LFD w/rosiglitazone: Drug rosiglitazone (Cayman Chemicals) was incorporated into low fat diet D12450B by Research Diets at 36mg/kg of diet. Mice received control low fat diet for 10 weeks (age 6-16 weeks), and the rosiglitazone-containing diet versus control diet for the final 2 weeks (until sacrifice at 18 weeks) LFD control for rosi: mice were fed a control low fat diet (Research Diet D12450B)影响疾病风险的单核苷酸多态性（Single Nucleotide Polymorphism, SNPs）通常位于非编码基因组区域。本研究证实，SNPs在小鼠品系选择性的脂肪组织过氧化物酶体增殖物激活受体γ（Peroxisome Proliferator-Activated Receptor Gamma, PPARγ）结合位点处显著富集；PPARγ是一类靶向抗糖尿病药物的核受体。此类SNPs中，许多可改变PPARγ或其协同因子的结合基序，并功能性调控邻近基因的表达——这些基因的表达呈现品系选择性，且在杂合F1小鼠中存在表达失衡。此外，PPARγ的遗传依赖性结合可解释噻唑烷二酮类（Thiazolidinediones, TZD）药物对小鼠的品系特异性转录效应，为基于核受体基因组占位的个性化医疗提供了概念验证。 在人类脂肪组织中，改变结合基序的SNPs可导致PPARγ结合差异，为部分表达数量性状位点（expression quantitative trait loci）提供了分子机制，同时在全基因组关联研究中成为代谢异常性状的风险因素。其中1个改变PPARγ结合基序的SNP与高密度脂蛋白（High-Density Lipoprotein, HDL）水平及其他代谢综合征参数相关。综上，PPARγ基因组结合占据的自然遗传变异决定了个体的疾病风险与药物响应。 本数据集包含两种饮食与脂肪沉积类型均存在差异的小鼠品系间的5组RNA测序（RNA Sequencing, RNA-seq）实验，其中1组实验用于评估罗格列酮的药物响应。我们的RNA-seq数据主要包含4组核心实验： 第一组实验：采集两种小鼠品系及其F1后代的样本，所有样本均取自同一脂肪沉积部位，且小鼠均饲喂相同的标准啮齿类饲料。 第二组实验包含两个子部分：第一部分采集两种小鼠品系在低脂饮食（Low Fat Diet, LFD）下的附睾白色脂肪组织（epididymal White Adipose Tissue, eWAT）样本，作为对照；第二部分则采集饲喂低脂饮食并联合给予罗格列酮的小鼠的对应附睾白色脂肪组织样本。 第三组实验：采集两种小鼠品系在低脂饮食下的附睾白色脂肪组织样本。 第四组实验：采集两种小鼠品系在低脂饮食下的腹股沟白色脂肪组织（inguinal White Adipose Tissue, iWAT）样本。 此外，本数据集还包含1份单独的全局运行-on测序（Global Run-On Sequencing, GRO-seq）样本，该实验以饲喂低脂饮食的B6品系小鼠的附睾白色脂肪组织为研究对象。 附实验参数说明： eWAT：附睾白色脂肪组织 iWAT：腹股沟白色脂肪组织 LFD-12w：小鼠饲喂对照低脂饲料（Research Diet D12450B） 标准饲料组：小鼠饲喂标准啮齿类饲料 LFD+罗格列酮组：罗格列酮（Cayman Chemicals公司产品）以36mg/kg饲料的比例被Research Diets公司添加至低脂饲料D12450B中；小鼠先饲喂对照低脂饲料10周（6~16周龄），最后2周分别饲喂含罗格列酮的低脂饲料或对照低脂饲料，直至18周龄时处死。 罗格列酮对照低脂饮食组：小鼠饲喂对照低脂饲料（Research Diet D12450B）