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 KesterenCheng Ming Chiang, Steve Lancel, Hélène Duez, Jean Sébastien Annicotte, Réjane Paumelle, Ilse Vanhorebeek, Greet Van den Berghe, Bart Staels, Philippe Lefebvre, Jérôme Eeckhoute

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article numbere9156
JournalMolecular Systems Biology
Volume16
Issue number5
DOIs
StatePublished - May 1 2020

Keywords

  • NFIL3
  • PAR-bZIP
  • liver injury
  • sepsis
  • super-enhancer

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)
  • Agricultural and Biological Sciences(all)
  • Applied Mathematics

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  • Cite this

    Dubois, V., Gheeraert, C., Vankrunkelsven, W., Dubois-Chevalier, J., Dehondt, H., Bobowski-Gerard, M., Vinod, M., Zummo, F. P., Güiza, F., Ploton, M., Dorchies, E., Pineau, L., Boulinguiez, A., Vallez, E., Woitrain, E., Baugé, E., Lalloyer, F., Duhem, C., Rabhi, N., ... Eeckhoute, J. (2020). Endoplasmic reticulum stress actively suppresses hepatic molecular identity in damaged liver. Molecular Systems Biology, 16(5), [e9156]. https://doi.org/10.15252/msb.20199156