GSE104302
Identification of LRH1-driven transcription factor circuitry for hepatocyte identity using cistromic analysis of super-enhancers
The gene expression circuitry that controls maintenance of normal liver physiology is poorly understood. Super-enhancers are known to contribute to mammalian cell identity. The injured liver loses normal functions, with concomitant decreased expression of key identity genes. Here, we identified core transcriptional regulators that are highly active in hepatocytes, using genome-wide analysis and hierarchical ordering of super-enhancer distribution. Using network analysis of super-enhancer-associated gene interactions and human GEO databases for liver diseases of various etiologies, we identified a super-enhancer-associated network, with core TFs of LRH1, HNF4a, PPARa and RXRa. In a mouse model, expression of core TFs was robustly inhibited by single or multiple challenge(s) with liver toxicant. Levels of LRH1 and PPARa were greatly diminished, whereas other TFs were moderately altered. In hepatocytes, overexpression of each core TF promoted induction of other core TFs, with recovery of hepatocyte identity. Particularly, LRH1 overexpression caused recovery of super-enhancer-associated signalling circuitry in liver-toxicant challenged mice, protecting against liver injury. Hepatic stellate cells showed a unique super-enhancer signature. Using cistromic analysis of gene expression, we identified a novel hepatocyte-specific transcriptional network, and found that LRH1 drives the positive feed-forward expression circuitry and expression of hepatocyte identity genes, improving our understanding of liver pathophysiology and identifying novel disease targets. Overall design: Examination of RNA expression in mouse livers treated with vehicle, APAP, or LRH1.