Cell Type-Resolved Genomic Profiling of NASH and liver fibrosis

We generated hepatocyte-specific profiles of the genomic landscapes during NASH progression using the INTACT methodology We fed male HEP-INTACT mice two different NASH-inducing diets, 20 weeks of a FPC diet (Wang et al., 2016) or 7 weeks of a CDAHFD (Matsumoto et al., 2013), and control mice were fed a low fat diet for the same periods. Mice that had been fed NASH-inducing diets were divided into two groups, a mild and advanced NASH group, based on the liver histology. Whereas both groups had high levels of steatosis and inflammation compared to the control group, only the advanced NASH group displayed a significant degree of liver fibrosis. Livers were subsequently subjected to INTACT followed by ATAC-seq analyses.本研究借助INTACT技术，构建了非酒精性脂肪性肝炎（NASH）进程中肝细胞特异性的基因组全景特征谱。我们为雄性HEP-INTACT小鼠饲喂两种不同的NASH诱导日粮：一是持续20周的FPC日粮（Wang等，2016），二是持续7周的CDAHFD日粮（Matsumoto等，2013）；同期对照组小鼠仅饲喂低脂日粮。根据肝脏组织学检测结果，饲喂NASH诱导日粮的小鼠被划分为轻度NASH组与晚期NASH组。相较于对照组，两组小鼠均出现高水平的肝脏脂肪变性与炎症反应，但仅晚期NASH组呈现出显著的肝纤维化特征。后续我们对肝脏样本依次开展INTACT技术处理与转座酶可及性染色质测序（ATAC-seq）分析。