Persistent chromatin modifications induced by high fat diet

Obesity is a highly heritable complex disease that results from the interaction of multiple genetic and environmental factors. Formerly obese individuals are susceptible to metabolic disorders later in life, even after lifestyle changes are made to mitigate the obese state. This is reminiscent of the metabolic memory phenomenon originally observed for persistent complications in diabetic patients, despite subsequent glycemic control. Epigenetic modifications represent a potential mediator of this observed memory. We previously demonstrated that a high fat (HF) diet leads to changes in chromatin accessibility in the mouse liver. The regions of greatest chromatin changes in accessibility are largely strain dependent, indicating a genetic component in diet-induced chromatin alterations. We have now examined the persistence of diet-induced chromatin accessibility changes upon diet reversal in two strains of mice. We find that a substantial fraction of loci that undergo chromatin accessibility changes with HF diet remain in the remodeled state after diet reversal in C57BL/6J mice. In contrast, the vast majority of diet-induced chromatin accessibility changes in A/J mice are transient. Our data also indicate that the persistent chromatin accessibility changes observed in C57BL/6J are associated with specific transcription factors and histone posttranslational modifications. The persistent loci identified here are likely to be contributing to the overall phenotype and are attractive targets for therapeutic intervention. Examination of chromatin remodeling with FAIRE-seq in livers of C57BL/6J and A/J mice on three diet regimen: 1) control diet for 16 weeks, 2) high fat diet for 16 weeks, or 3) high fat diet for 8 weeks with control diet for 8 weeks. These chromatin profiles were complemented with gene expression data (RNA-seq)肥胖是一种高度可遗传的复杂疾病，由多种遗传与环境因素相互作用共同引发。既往肥胖个体即便通过调整生活方式改善了肥胖状态，晚年仍易罹患代谢紊乱类疾病。这与最初在糖尿病患者中观察到的代谢记忆现象高度相似——即便后续实现血糖控制，患者仍会出现持续性并发症。表观遗传修饰（epigenetic modifications）或是这一记忆现象的潜在介导因子。 我们此前的研究已证实，高脂（high fat, HF）饮食会改变小鼠肝脏的染色质可及性（chromatin accessibility）。染色质可及性变化最为显著的区域在很大程度上依赖于小鼠品系，这表明饮食诱导的染色质改变存在遗传基础。 本研究现已针对两种品系小鼠，探究了饮食逆转后，饮食诱导的染色质可及性变化的持续性。 我们发现，在C57BL/6J小鼠中，随高脂饮食发生染色质可及性改变的大量基因位点，在饮食逆转后仍维持染色质重塑状态。与之形成鲜明对比的是，A/J小鼠中绝大多数饮食诱导的染色质可及性变化均为暂时性的。 我们的数据分析还显示，C57BL/6J小鼠中观察到的持续性染色质可及性变化，与特定转录因子及组蛋白翻译后修饰密切相关。本研究鉴定出的持续性染色质位点，可能参与调控整体代谢表型，同时也是治疗干预的极具吸引力的靶点。 我们对分别处于三种饮食方案下的C57BL/6J与A/J小鼠肝脏开展了FAIRE-seq（甲醛辅助分离调控元件测序）染色质重塑分析：1）正常饮食干预16周；2）高脂饮食干预16周；3）先以高脂饮食干预8周，随后切换为正常饮食干预8周。上述染色质图谱还结合了基因表达数据（RNA-seq）进行补充分析。