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Title: NR2E3 is a key component in p53 activation by regulating a long noncoding RNA DINO in acute liver injuries.

Authors: Khanal, Tilak; Leung, Yuet-Kin; Jiang, Wang; Timchenko, Nicolai; Ho, Shuk-Mei; Kim, Kyounghyun

Published In FASEB J, (2019 07)

Abstract: Damage-induced long noncoding RNA (DINO) is a long noncoding RNA that directly interacts with p53 and thereby enhances p53 stability and activity in response to various cellular stresses. Here, we demonstrate that nuclear receptor subfamily 2 group E member 3 (NR2E3) plays a crucial role in maintaining active DINO epigenetic status for its proper induction and subsequent p53 activation. In acetaminophen (APAP)- or carbon tetrachloride-induced acute liver injuries, NR2E3 knockout (KO) mice exhibited far more severe liver injuries due to impaired DINO induction and p53 activation. Mechanistically, NR2E3 loss both in vivo and in vitro induced epigenetic DINO repression accompanied by reduced DINO chromatin accessibility. Furthermore, compared with the efficient reversal by a typical antidote N-acetylcysteine (NAC) treatment of APAP-induced liver injury in wild-type mice, the liver injury of NR2E3 KO mice was not effectively reversed, indicating that an intact NR2E3-DINO-p53-signaling axis is essential for NAC-mediated recovery against APAP-induced hepatotoxicity. These findings establish that NR2E3 is a critical component in p53 activation and a novel susceptibility factor to drug- or toxicant-induced acute liver injuries.-Khanal, T., Leung, Y.-K., Jiang, W., Timchenko, N., Ho, S.-M., Kim, K. NR2E3 is a key component in p53 activation by regulating a long noncoding RNA DINO in acute liver injuries.

PubMed ID: 30991008 Exiting the NIEHS site

MeSH Terms: Acetaminophen/adverse effects; Acetaminophen/pharmacology; Acetylcysteine/pharmacology; Animals; Chemical and Drug Induced Liver Injury/genetics; Chemical and Drug Induced Liver Injury/metabolism*; Chemical and Drug Induced Liver Injury/pathology; Epigenesis, Genetic/drug effects; Hep G2 Cells; Humans; Liver Failure, Acute/chemically induced; Liver Failure, Acute/genetics; Liver Failure, Acute/metabolism*; Liver Failure, Acute/pathology; Mice; Mice, Knockout; Orphan Nuclear Receptors/genetics; Orphan Nuclear Receptors/metabolism*; RNA, Long Noncoding/biosynthesis*; RNA, Long Noncoding/genetics; Signal Transduction*; Tumor Suppressor Protein p53/genetics; Tumor Suppressor Protein p53/metabolism*

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