LRH1-driven transcription factor circuitry for hepatocyte identity: Super-enhancer cistromic analysis
- Authors
- Joo, Min Sung; Koo, Ja Hyun; Kim, Tae Hyun; Kim, Yun Seok; Kim, Sang Geon
- Issue Date
- Feb-2019
- Publisher
- Elsevier B.V.
- Citation
- EBioMedicine, v.40, pp 488 - 503
- Pages
- 16
- Journal Title
- EBioMedicine
- Volume
- 40
- Start Page
- 488
- End Page
- 503
- URI
- https://scholarworks.sookmyung.ac.kr/handle/2020.sw.sookmyung/159355
- DOI
- 10.1016/j.ebiom.2018.12.056
- ISSN
- 2352-3964
2352-3964
- Abstract
- Background: The injured liver loses normal function, with concomitant decrease of key identity genes. Super-enhancers contribute to mammalian cell identity. Here, we identified core transcription factors (TFs) that are active in hepatocytes, using genome-wide analysis and hierarchical ordering of super-enhancer distribution. Methods: Expression of core TFs was assessed in a cohort of patients with hepatitis or cirrhosis and animal models. Quantitative PCR, chromatin immunoprecipitation assays, and hydrodynamic gene delivery methods were used to assess gene regulation and hepatocyte viability. RNA-sequencing data were generated to investigate the role of LRH1 in hepatocyte protection from injury. Results: Network analysis of super-enhancer-associated gene interactions and expression arrays for cohorts of patients with hepatitis and cirrhosis enabled us to identify a super-enhancer-associated network, and LRH1, HNF4α, PPARα, and RXRα as core TFs. In mouse models, expression of core TFs was robustly inhibited by single and multiple challenge(s) with liver toxicant. RNA-seq analysis revealed changes in expression in the super-enhancer-associated genes sensitively biased toward repression by intoxication. LRH1 gene delivery prevented the loss of hepatic super-enhancer-associated signaling circuitry in toxicant-challe
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