Precision pharmacological reversal of strain-specific diet-induced metabolic syndrome in mice informed by epigenetic and transcriptional regulation. Precision pharmacological reversal of strain-specific diet-induced metabolic syndrome in mice informed by epigenetic and transcriptional regulation

We exposed three mouse strains to a high-fat high-carbohydrate diet, leading to varying degrees of metabolic syndrome. Comprehensive methylation and transcriptomic analysis found overlapping but also highly divergent changes in DNA methylation and gene expression, with pathway analysis suggesting a strategy for strain-specific targeted pharmacologic intervention of upstream regulators. Administeration of the drug GW4064 to target one of these genotype-dependent networks, the farnesoid X receptor pathway resulted in genotype-specific protection against dietary effects in BL6 as predicted by our epigenetic analysis. Overall design: WGBS and RNA-Seq was performed on BL6, A/J, and NOD mice fed Standard or American diets. Some mice were also administered DMSO vehicle or the FXR agonist GW4064.

本研究将三种品系小鼠暴露于高脂高糖饮食条件下，诱导其产生不同程度的代谢综合征（metabolic syndrome）。通过全面的甲基化组与转录组分析，我们发现DNA甲基化与基因表达既存在重叠的变化特征，也呈现高度分化的差异；通路分析结果提示，可针对品系特异性的上游调控因子制定靶向药物干预策略。我们靶向其中一类基因型依赖的调控网络——法尼醇X受体（farnesoid X receptor，FXR）通路，给予药物GW4064干预，结果在BL6小鼠中实现了如表观遗传分析预测的、基因型特异性的饮食诱导损伤防护效果。总体实验设计：对饲喂标准饲料或美式饲料的BL6、A/J及NOD小鼠开展全基因组亚硫酸氢盐测序（Whole Genome Bisulfite Sequencing，WGBS）与转录组测序（RNA Sequencing，RNA-Seq）；部分小鼠还被给予二甲基亚砜（Dimethyl sulfoxide，DMSO）溶剂对照或FXR激动剂GW4064。