Endoplasmic reticulum stress actively suppresses hepatic molecular identity in damaged liver

• Published in: Molecular systems biology Vol. 16; no. 5; pp. e9156 - n/a
• Main Authors: Dubois, Vanessa, Gheeraert, Céline, Vankrunkelsven, Wouter, Dubois‐Chevalier, Julie, Dehondt, Hélène, Bobowski‐Gerard, Marie, Vinod, Manjula, Zummo, Francesco Paolo, Güiza, Fabian, Ploton, Maheul, Dorchies, Emilie, Pineau, Laurent, Boulinguiez, Alexis, Vallez, Emmanuelle, Woitrain, Eloise, Baugé, Eric, Lalloyer, Fanny, Duhem, Christian, Rabhi, Nabil, van Kesteren, Ronald E, Chiang, Cheng‐Ming, Lancel, Steve, Duez, Hélène, Annicotte, Jean‐Sébastien, Paumelle, Réjane, Vanhorebeek, Ilse, Van den Berghe, Greet, Staels, Bart, Lefebvre, Philippe, Eeckhoute, Jérôme
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.05.2020; EMBO Press; John Wiley and Sons Inc; Springer Nature
• Subjects: Animal models; Animals; Basic-Leucine Zipper Transcription Factors - genetics; Basic-Leucine Zipper Transcription Factors - metabolism; Binding sites; Biochemistry, Molecular Biology; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Cell Line; Cells, Cultured; Chemical and Drug Induced Liver Injury - genetics; Chemical and Drug Induced Liver Injury - metabolism; Chromatin Immunoprecipitation Sequencing; Collaboration; Down-Regulation; EMBO09; Endoplasmic reticulum; Endoplasmic Reticulum Stress - drug effects; Endoplasmic Reticulum Stress - genetics; Enhancers; Gene expression; Gene Expression Profiling; Gene Expression Regulation - genetics; Gene Regulatory Networks; Genomics; Hepatocytes - drug effects; Hepatocytes - metabolism; Humans; Kinases; Life Sciences; Liver; Liver diseases; Liver Diseases - genetics; Liver Diseases - metabolism; liver injury; Male; Metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Molecular biology; NFIL3; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; PAR‐bZIP; Physiology; Proteins; Regeneration; Regulatory sequences; Repair; Sepsis; super‐enhancer; Thapsigargin - toxicity; Transcription Factors - genetics; Transcription Factors - metabolism; Transcriptome - genetics; Up-Regulation; PAR‐bZIP; super‐enhancer; liver injury; NFIL3; sepsis; PAR-bZIP; super-enhancer
• ISSN: 1744-4292; 1744-4292
• DOI: 10.15252/msb.20199156

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. Synopsis 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. Acute ERS induces loss of hepatic molecular identity by extensively and preferentially downregulating liver identity (LIVER‐ID) genes. ERS‐mediated transcriptional repression is an active process involving changes in the transcription factor repertoire with inhibition of the LIVER‐ID network and induction of the NFIL3 repressor. This translates into a global loss of activity of cis ‐regulatory modules densely co‐bound by LIVER‐ID transcription factors and decommissioning of BRD4 at super‐enhancers. The hepatic and ERS transcriptional programs are in competitive equilibrium with direct relevance towards the liver's ability to recover from injury. Graphical Abstract 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.