Time-resolved cartography of the hepatic methylome and transcriptome during type 2 diabetes pathogenesis

2型糖尿病(T2D)与许多疾病相关器官的表观遗传学改变有关。然而，目前尚不清楚调控失调的表观基因组是否在糖尿病病理中起因果作用。此外，需要更好地了解在分化的细胞中是否可以在一生中获得非生理性表观遗传标记，而不是子宫内编程和表观遗传。本研究旨在通过全基因组亚硫酸盐测序(WGBS)和RNA测序(RNA-seq)研究胰岛素抵抗诱导过程中肝脏甲基化组和转录组随时间的变化。以高脂饲料喂养小鼠1、2、4、5周(n=5/组)诱导肥胖和胰岛素抵抗。饲喂饲料的小鼠作为对照组。监测代谢参数，包括葡萄糖耐量、体重、血浆胰岛素和肝甘油三酯。因此，可以解决哪些饮食诱导的肝脏甲基组变化在胰岛素抵抗出现之前发生。同时，对36名肥胖的2型糖尿病患者和60名肥胖的非糖尿病受试者的肝脏甲基组和转录组进行WGBS和RNA-seq分析。对小鼠和人类的纵向和横断面数据的比较将确定与T2D病因学相关的基因和表观遗传标记，这些基因和表观遗传标记可能在人类T2D病理中发挥重要作用。

Type 2 diabetes (T2D) is associated with epigenetic alterations in many disease relevant organs. However, it remains unclear if the dysregulated epigenome causally contributes to diabetes pathology. Moreover, it needs to be better understood if diabetogenic epigenetic marks can be acquired in differentiated cells during a life time as opposed to in utero programming and epigenetic inheritance. This proposal aims to investigate the time-resolved hepatic methylome and transcriptome by whole genome bisulphite sequencing (WGBS) and RNA sequencing (RNA-seq) in liver during induction of insulin resistance. Mice are fed with high-fat diet to induce diet-induced obesity and insulin resistance for 1, 2, 4 and 5 weeks (n=5/group). Chow-fed mice serve as a control group. Metabolic parameters including glucose tolerance, body weight, plasma insulin and hepatic triglycerides are monitored. Thereby it can be tackled which diet-induced changes in the hepatic methylome occur before manifestation of insulin resistance. In parallel the hepatic methylome and transcriptome of 36 obese T2-diabetic and 60 obese non-diabetic subjects will be analysed by WGBS and RNA-seq. Comparison of the longitudinal murine and cross-sectional human data will identify genes and epigenetic marks that are causally involved in T2D aetiology and that could play an important role in the human T2D pathology.