Endoplasmic reticulum stress actively suppresses hepatic molecular identity in damaged liver
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 part...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Springer Nature
2020-05-01
|
| Series: | Molecular Systems Biology |
| Subjects: | |
| Online Access: | https://doi.org/10.15252/msb.20199156 |
| _version_ | 1797281933060734976 |
|---|---|
| author | Vanessa Dubois Céline Gheeraert Wouter Vankrunkelsven Julie Dubois‐Chevalier Hélène Dehondt Marie Bobowski‐Gerard Manjula Vinod Francesco Paolo Zummo Fabian Güiza Maheul Ploton Emilie Dorchies Laurent Pineau Alexis Boulinguiez Emmanuelle Vallez Eloise Woitrain Eric Baugé Fanny Lalloyer Christian Duhem Nabil Rabhi Ronald E van Kesteren Cheng‐Ming Chiang Steve Lancel Hélène Duez Jean‐Sébastien Annicotte Réjane Paumelle Ilse Vanhorebeek Greet Van den Berghe Bart Staels Philippe Lefebvre Jérôme Eeckhoute |
| author_facet | Vanessa Dubois Céline Gheeraert Wouter Vankrunkelsven Julie Dubois‐Chevalier Hélène Dehondt Marie Bobowski‐Gerard Manjula Vinod Francesco Paolo Zummo Fabian Güiza Maheul Ploton Emilie Dorchies Laurent Pineau Alexis Boulinguiez Emmanuelle Vallez Eloise Woitrain Eric Baugé Fanny Lalloyer Christian Duhem Nabil Rabhi Ronald E van Kesteren Cheng‐Ming Chiang Steve Lancel Hélène Duez Jean‐Sébastien Annicotte Réjane Paumelle Ilse Vanhorebeek Greet Van den Berghe Bart Staels Philippe Lefebvre Jérôme Eeckhoute |
| author_sort | Vanessa Dubois |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-07T17:04:36Z |
| format | Article |
| id | doaj.art-25e5ed41e1224b8fae474a62d14c30b5 |
| institution | Directory Open Access Journal |
| issn | 1744-4292 |
| language | English |
| last_indexed | 2024-03-07T17:04:36Z |
| publishDate | 2020-05-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | Molecular Systems Biology |
| spelling | doaj.art-25e5ed41e1224b8fae474a62d14c30b52024-03-03T02:48:20ZengSpringer NatureMolecular Systems Biology1744-42922020-05-01165n/an/a10.15252/msb.20199156Endoplasmic reticulum stress actively suppresses hepatic molecular identity in damaged liverVanessa Dubois0Céline Gheeraert1Wouter Vankrunkelsven2Julie Dubois‐Chevalier3Hélène Dehondt4Marie Bobowski‐Gerard5Manjula Vinod6Francesco Paolo Zummo7Fabian Güiza8Maheul Ploton9Emilie Dorchies10Laurent Pineau11Alexis Boulinguiez12Emmanuelle Vallez13Eloise Woitrain14Eric Baugé15Fanny Lalloyer16Christian Duhem17Nabil Rabhi18Ronald E van Kesteren19Cheng‐Ming Chiang20Steve Lancel21Hélène Duez22Jean‐Sébastien Annicotte23Réjane Paumelle24Ilse Vanhorebeek25Greet Van den Berghe26Bart Staels27Philippe Lefebvre28Jérôme Eeckhoute29Inserm, CHU Lille Institut Pasteur de Lille U1011‐EGID University of Lille Lille FranceInserm, CHU Lille Institut Pasteur de Lille U1011‐EGID University of Lille Lille FranceClinical Division and Laboratory of Intensive Care Medicine Department of Cellular and Molecular Medicine KU Leuven Leuven BelgiumInserm, CHU Lille Institut Pasteur de Lille U1011‐EGID University of Lille Lille FranceInserm, CHU Lille Institut Pasteur de Lille U1011‐EGID University of Lille Lille FranceInserm, CHU Lille Institut Pasteur de Lille U1011‐EGID University of Lille Lille FranceInserm, CHU Lille Institut Pasteur de Lille U1011‐EGID University of Lille Lille FranceInserm, CHU Lille Institut Pasteur de Lille U1011‐EGID University of Lille Lille FranceClinical Division and Laboratory of Intensive Care Medicine Department of Cellular and Molecular Medicine KU Leuven Leuven BelgiumInserm, CHU Lille Institut Pasteur de Lille U1011‐EGID University of Lille Lille FranceInserm, CHU Lille Institut Pasteur de Lille U1011‐EGID University of Lille Lille FranceInserm, CHU Lille Institut Pasteur de Lille U1011‐EGID University of Lille Lille FranceInserm, CHU Lille Institut Pasteur de Lille U1011‐EGID University of Lille Lille FranceInserm, CHU Lille Institut Pasteur de Lille U1011‐EGID University of Lille Lille FranceInserm, CHU Lille Institut Pasteur de Lille U1011‐EGID University of Lille Lille FranceInserm, CHU Lille Institut Pasteur de Lille U1011‐EGID University of Lille Lille FranceInserm, CHU Lille Institut Pasteur de Lille U1011‐EGID University of Lille Lille FranceInserm, CHU Lille Institut Pasteur de Lille U1011‐EGID University of Lille Lille FranceUMR 8199 ‐ EGID CNRS Institut Pasteur de Lille University of Lille Lille FranceCenter for Neurogenomics and Cognitive Research Neuroscience Campus Amsterdam VU University Amsterdam The NetherlandsSimmons Comprehensive Cancer Center Departments of Biochemistry and Pharmacology University of Texas Southwestern Medical Center Dallas TX USAInserm, CHU Lille Institut Pasteur de Lille U1011‐EGID University of Lille Lille FranceInserm, CHU Lille Institut Pasteur de Lille U1011‐EGID University of Lille Lille FranceUMR 8199 ‐ EGID CNRS Institut Pasteur de Lille University of Lille Lille FranceInserm, CHU Lille Institut Pasteur de Lille U1011‐EGID University of Lille Lille FranceClinical Division and Laboratory of Intensive Care Medicine Department of Cellular and Molecular Medicine KU Leuven Leuven BelgiumClinical Division and Laboratory of Intensive Care Medicine Department of Cellular and Molecular Medicine KU Leuven Leuven BelgiumInserm, CHU Lille Institut Pasteur de Lille U1011‐EGID University of Lille Lille FranceInserm, CHU Lille Institut Pasteur de Lille U1011‐EGID University of Lille Lille FranceInserm, CHU Lille Institut Pasteur de Lille U1011‐EGID University of Lille Lille FranceAbstract 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.https://doi.org/10.15252/msb.20199156liver injuryNFIL3PAR‐bZIPsepsissuper‐enhancer |
| spellingShingle | Vanessa Dubois Céline Gheeraert Wouter Vankrunkelsven Julie Dubois‐Chevalier Hélène Dehondt Marie Bobowski‐Gerard Manjula Vinod Francesco Paolo Zummo Fabian Güiza Maheul Ploton Emilie Dorchies Laurent Pineau Alexis Boulinguiez Emmanuelle Vallez Eloise Woitrain Eric Baugé Fanny Lalloyer Christian Duhem Nabil Rabhi Ronald E van Kesteren Cheng‐Ming Chiang Steve Lancel Hélène Duez Jean‐Sébastien Annicotte Réjane Paumelle Ilse Vanhorebeek Greet Van den Berghe Bart Staels Philippe Lefebvre Jérôme Eeckhoute Endoplasmic reticulum stress actively suppresses hepatic molecular identity in damaged liver Molecular Systems Biology liver injury NFIL3 PAR‐bZIP sepsis super‐enhancer |
| title | Endoplasmic reticulum stress actively suppresses hepatic molecular identity in damaged liver |
| title_full | Endoplasmic reticulum stress actively suppresses hepatic molecular identity in damaged liver |
| title_fullStr | Endoplasmic reticulum stress actively suppresses hepatic molecular identity in damaged liver |
| title_full_unstemmed | Endoplasmic reticulum stress actively suppresses hepatic molecular identity in damaged liver |
| title_short | Endoplasmic reticulum stress actively suppresses hepatic molecular identity in damaged liver |
| title_sort | endoplasmic reticulum stress actively suppresses hepatic molecular identity in damaged liver |
| topic | liver injury NFIL3 PAR‐bZIP sepsis super‐enhancer |
| url | https://doi.org/10.15252/msb.20199156 |
| work_keys_str_mv | AT vanessadubois endoplasmicreticulumstressactivelysuppresseshepaticmolecularidentityindamagedliver AT celinegheeraert endoplasmicreticulumstressactivelysuppresseshepaticmolecularidentityindamagedliver AT woutervankrunkelsven endoplasmicreticulumstressactivelysuppresseshepaticmolecularidentityindamagedliver AT julieduboischevalier endoplasmicreticulumstressactivelysuppresseshepaticmolecularidentityindamagedliver AT helenedehondt endoplasmicreticulumstressactivelysuppresseshepaticmolecularidentityindamagedliver AT mariebobowskigerard endoplasmicreticulumstressactivelysuppresseshepaticmolecularidentityindamagedliver AT manjulavinod endoplasmicreticulumstressactivelysuppresseshepaticmolecularidentityindamagedliver AT francescopaolozummo endoplasmicreticulumstressactivelysuppresseshepaticmolecularidentityindamagedliver AT fabianguiza endoplasmicreticulumstressactivelysuppresseshepaticmolecularidentityindamagedliver AT maheulploton endoplasmicreticulumstressactivelysuppresseshepaticmolecularidentityindamagedliver AT emiliedorchies endoplasmicreticulumstressactivelysuppresseshepaticmolecularidentityindamagedliver AT laurentpineau endoplasmicreticulumstressactivelysuppresseshepaticmolecularidentityindamagedliver AT alexisboulinguiez endoplasmicreticulumstressactivelysuppresseshepaticmolecularidentityindamagedliver AT emmanuellevallez endoplasmicreticulumstressactivelysuppresseshepaticmolecularidentityindamagedliver AT eloisewoitrain endoplasmicreticulumstressactivelysuppresseshepaticmolecularidentityindamagedliver AT ericbauge endoplasmicreticulumstressactivelysuppresseshepaticmolecularidentityindamagedliver AT fannylalloyer endoplasmicreticulumstressactivelysuppresseshepaticmolecularidentityindamagedliver AT christianduhem endoplasmicreticulumstressactivelysuppresseshepaticmolecularidentityindamagedliver AT nabilrabhi endoplasmicreticulumstressactivelysuppresseshepaticmolecularidentityindamagedliver AT ronaldevankesteren endoplasmicreticulumstressactivelysuppresseshepaticmolecularidentityindamagedliver AT chengmingchiang endoplasmicreticulumstressactivelysuppresseshepaticmolecularidentityindamagedliver AT stevelancel endoplasmicreticulumstressactivelysuppresseshepaticmolecularidentityindamagedliver AT heleneduez endoplasmicreticulumstressactivelysuppresseshepaticmolecularidentityindamagedliver AT jeansebastienannicotte endoplasmicreticulumstressactivelysuppresseshepaticmolecularidentityindamagedliver AT rejanepaumelle endoplasmicreticulumstressactivelysuppresseshepaticmolecularidentityindamagedliver AT ilsevanhorebeek endoplasmicreticulumstressactivelysuppresseshepaticmolecularidentityindamagedliver AT greetvandenberghe endoplasmicreticulumstressactivelysuppresseshepaticmolecularidentityindamagedliver AT bartstaels endoplasmicreticulumstressactivelysuppresseshepaticmolecularidentityindamagedliver AT philippelefebvre endoplasmicreticulumstressactivelysuppresseshepaticmolecularidentityindamagedliver AT jeromeeeckhoute endoplasmicreticulumstressactivelysuppresseshepaticmolecularidentityindamagedliver |