1. Endoplasmic reticulum stress actively suppresses hepatic molecular identity in damaged liver
- Author
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Dubois, Vanessa, Gheeraert, Celine, Vankrunkelsven, Wouter, Dubois-Chevalier, Julie, Dehondt, Helene, Bobowski-Gerard, Marie, Vinod, Manjula, Zummo, Francesco Paolo, Guiza, Fabian, Ploton, Maheul, Dorchies, Emilie, Pineau, Laurent, Boulinguiez, Alexis, Vallez, Emmanuelle, Woitrain, Eloise, Bauge, Eric, Lalloyer, Fanny, Duhem, Christian, Rabhi, Nabil, van Kesteren, Ronald E, Chiang, Cheng-Ming, Lancel, Steve, Duez, Helene, Annicotte, Jean-Sebastien, Paumelle, Rejane, Vanhorebeek, Ilse, Van den Berghe, Greet, Staels, Bart, Lefebvre, Philippe, Eeckhoute, Jerome, Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 (RNMCD), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Department of Intensive care Medicine [Leuven, Belgium], Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (EGENODIA (GI3M)), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Center for Neurogenomics and Cognitive Research [Amsterdam], Harold C. Simmons Comprehensive Cancer Center [Dallas, TX, États-Unis], University of Texas Southwestern Medical Center [Dallas], European Project: 694717,H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) ,ImmunoBile(2016), Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (GI3M), Derudas, Marie-Hélène, Bile acid, immune-metabolism, lipid and glucose homeostasis - ImmunoBile - - H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) 2016-09-01 - 2021-08-31 - 694717 - VALID, Molecular and Cellular Neurobiology, and Amsterdam Neuroscience - Neurodegeneration
- Subjects
Male ,Medicine (General) ,Cell Cycle Proteins ,[SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology ,Chromatin, Epigenetics, Genomics & Functional Genomics ,ACTIVATION ,sepsis ,Mice ,ENRICHMENT ANALYSIS ,BINDING ,Medicine and Health Sciences ,Gene Regulatory Networks ,Biology (General) ,Cells, Cultured ,GENE-EXPRESSION ,Mice, Knockout ,Liver Diseases ,Nuclear Proteins ,super‐enhancer ,Articles ,CELL IDENTITY ,Endoplasmic Reticulum Stress ,PAR-bZIP ,Up-Regulation ,TRANSCRIPTION FACTORS ,Basic-Leucine Zipper Transcription Factors ,Chromatin Immunoprecipitation Sequencing ,Thapsigargin ,Chemical and Drug Induced Liver Injury ,liver injury ,ACETYLATION ,QH301-705.5 ,DATABASE ,Down-Regulation ,Article ,Cell Line ,R5-920 ,SDG 3 - Good Health and Well-being ,NFIL3 ,super-enhancer ,Animals ,Humans ,ELONGATION ,Gene Expression Profiling ,PAR‐bZIP ,[SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology ,UNFOLDED PROTEIN ,Mice, Inbred C57BL ,Gene Expression Regulation ,Hepatocytes ,Transcriptome ,Transcription Factors - Abstract
Liver injury triggers adaptive remodeling of the hepatic transcriptome for repair/regeneration. We demonstrate that this involves particularly profound transcriptomic alterations where acute induction of genes involved in handling of endoplasmic reticulum stress (ERS) is accompanied by partial hepatic dedifferentiation. Importantly, widespread hepatic gene downregulation could not simply be ascribed to cofactor squelching secondary to ERS gene induction, but rather involves a combination of active repressive mechanisms. ERS acts through inhibition of the liver‐identity (LIVER‐ID) transcription factor (TF) network, initiated by rapid LIVER‐ID TF protein loss. In addition, induction of the transcriptional repressor NFIL3 further contributes to LIVER‐ID gene repression. Alteration to the liver TF repertoire translates into compromised activity of regulatory regions characterized by the densest co‐recruitment of LIVER‐ID TFs and decommissioning of BRD4 super‐enhancers driving hepatic identity. While transient repression of the hepatic molecular identity is an intrinsic part of liver repair, sustained disequilibrium between the ERS and LIVER‐ID transcriptional programs is linked to liver dysfunction as shown using mouse models of acute liver injury and livers from deceased human septic patients., Functional genomics analyses shows that acute endoplasmic reticulum stress (ERS) in the liver induces a global loss of molecular identity and partial hepatic dedifferentiation, which characterize mouse and human liver upon acute injury.
- Published
- 2020