Developmentally regulated isoform of HNF4a reprograms the adult liver

Hepatocyte Nuclear Factor 4a (HNF4a), master regulator of hepatocyte differentiation, is regulated by two promoters (P1 and P2). P1-HNF4a but not P2-HNF4a is expressed in normal adult liver in fed conditions. Both P1- and P2-HNF4a are expressed in fetal liver. P2-HNF4a expression is increased in fasted conditions, high fat diet, alcoholic liver and liver cancer. To determine the target genes of the P1- and P2-HNF4a isoforms, we compared P2-HNF4a-expressing exon swap mice (a7HMZ) to wildtype (WT) male mice. Liver ChIP-seq samples were taken at 10:30 AM (ZT 3.5) Overall design: Liver ChIP-seq samples from adult WT (P1-HNF4a1) and a7HMZ (P2-HNF4a7) male mice were analyzed in triplicate at 10:30 AM (ZT 3.5).

肝细胞核因子4α（Hepatocyte Nuclear Factor 4a, HNF4a）是肝细胞分化的核心调控主因子，受两个启动子（P1与P2）调控。进食状态下，正常成年肝脏仅表达P1-HNF4a而非P2-HNF4a；胎肝中则同时存在P1-与P2-HNF4a的表达。P2-HNF4a的表达在禁食状态、高脂饮食、酒精性肝病及肝癌中均显著上调。为明确P1与P2-HNF4a亚型的靶基因，本研究将表达P2-HNF4a的外显子置换小鼠（exon swap mice）a7HMZ与野生型（wildtype, WT）雄性小鼠进行对照分析。于上午10:30（ZT 3.5）采集肝脏组织进行染色质免疫共沉淀测序（ChIP-seq）。整体实验设计如下：于上午10:30（ZT 3.5）对成年野生型（P1-HNF4a1）与a7HMZ（P2-HNF4a7）雄性小鼠的肝脏ChIP-seq样本进行三次生物学重复分析。