Developmentally regulated isoform of HNF4α reprograms the adult liver

Hepatocyte Nuclear Factor 4α (HNF4α), master regulator of hepatocyte differentiation, is regulated by two promoters (P1 and P2). P1-HNF4α but not P2-HNF4α is expressed in normal adult liver while both P1- and P2-HNF4α are expressed in fetal liver and liver cancer. To determine the physiological function of the HNF4α isoforms, we compared P2-HNF4α-expressing exon swap mice to wildtype (WT) using RNA-seq, ChIP-seq, proteomics, protein binding microarrays (PBMs) and metabolomics. P2-HNF4α orchestrates a distinct transcriptomic and metabolomic profile. Liver RNA-seq samples from both genotypes (WT and a7HMZ, P1- and P2-HNF4α respectively) were taken at three time-points as well as a 12-hr fast with both genotypes at the earliest time-point. Please note that three different time points are indicated in the sample titles as the time of the day, in 24hr notation (i.e. 1030 = 10:30am, 1330 = 1:30pm, and 2030 = 8:30pm).