Molecular Systems Biology (May 2020)
Endoplasmic reticulum stress actively suppresses hepatic molecular identity in damaged liver
- 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
Affiliations
- Vanessa Dubois
- Inserm, CHU Lille Institut Pasteur de Lille U1011‐EGID University of Lille Lille France
- Céline Gheeraert
- Inserm, CHU Lille Institut Pasteur de Lille U1011‐EGID University of Lille Lille France
- Wouter Vankrunkelsven
- Clinical Division and Laboratory of Intensive Care Medicine Department of Cellular and Molecular Medicine KU Leuven Leuven Belgium
- Julie Dubois‐Chevalier
- Inserm, CHU Lille Institut Pasteur de Lille U1011‐EGID University of Lille Lille France
- Hélène Dehondt
- Inserm, CHU Lille Institut Pasteur de Lille U1011‐EGID University of Lille Lille France
- Marie Bobowski‐Gerard
- Inserm, CHU Lille Institut Pasteur de Lille U1011‐EGID University of Lille Lille France
- Manjula Vinod
- Inserm, CHU Lille Institut Pasteur de Lille U1011‐EGID University of Lille Lille France
- Francesco Paolo Zummo
- Inserm, CHU Lille Institut Pasteur de Lille U1011‐EGID University of Lille Lille France
- Fabian Güiza
- Clinical Division and Laboratory of Intensive Care Medicine Department of Cellular and Molecular Medicine KU Leuven Leuven Belgium
- Maheul Ploton
- Inserm, CHU Lille Institut Pasteur de Lille U1011‐EGID University of Lille Lille France
- Emilie Dorchies
- Inserm, CHU Lille Institut Pasteur de Lille U1011‐EGID University of Lille Lille France
- Laurent Pineau
- Inserm, CHU Lille Institut Pasteur de Lille U1011‐EGID University of Lille Lille France
- Alexis Boulinguiez
- Inserm, CHU Lille Institut Pasteur de Lille U1011‐EGID University of Lille Lille France
- Emmanuelle Vallez
- Inserm, CHU Lille Institut Pasteur de Lille U1011‐EGID University of Lille Lille France
- Eloise Woitrain
- Inserm, CHU Lille Institut Pasteur de Lille U1011‐EGID University of Lille Lille France
- Eric Baugé
- Inserm, CHU Lille Institut Pasteur de Lille U1011‐EGID University of Lille Lille France
- Fanny Lalloyer
- Inserm, CHU Lille Institut Pasteur de Lille U1011‐EGID University of Lille Lille France
- Christian Duhem
- Inserm, CHU Lille Institut Pasteur de Lille U1011‐EGID University of Lille Lille France
- Nabil Rabhi
- UMR 8199 ‐ EGID CNRS Institut Pasteur de Lille University of Lille Lille France
- Ronald E van Kesteren
- Center for Neurogenomics and Cognitive Research Neuroscience Campus Amsterdam VU University Amsterdam The Netherlands
- Cheng‐Ming Chiang
- Simmons Comprehensive Cancer Center Departments of Biochemistry and Pharmacology University of Texas Southwestern Medical Center Dallas TX USA
- Steve Lancel
- Inserm, CHU Lille Institut Pasteur de Lille U1011‐EGID University of Lille Lille France
- Hélène Duez
- Inserm, CHU Lille Institut Pasteur de Lille U1011‐EGID University of Lille Lille France
- Jean‐Sébastien Annicotte
- UMR 8199 ‐ EGID CNRS Institut Pasteur de Lille University of Lille Lille France
- Réjane Paumelle
- Inserm, CHU Lille Institut Pasteur de Lille U1011‐EGID University of Lille Lille France
- Ilse Vanhorebeek
- Clinical Division and Laboratory of Intensive Care Medicine Department of Cellular and Molecular Medicine KU Leuven Leuven Belgium
- Greet Van den Berghe
- Clinical Division and Laboratory of Intensive Care Medicine Department of Cellular and Molecular Medicine KU Leuven Leuven Belgium
- Bart Staels
- Inserm, CHU Lille Institut Pasteur de Lille U1011‐EGID University of Lille Lille France
- Philippe Lefebvre
- Inserm, CHU Lille Institut Pasteur de Lille U1011‐EGID University of Lille Lille France
- Jérôme Eeckhoute
- Inserm, CHU Lille Institut Pasteur de Lille U1011‐EGID University of Lille Lille France
- DOI
- https://doi.org/10.15252/msb.20199156
- Journal volume & issue
-
Vol. 16,
no. 5
pp. n/a – n/a
Abstract
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.
Keywords