Endoplasmic reticulum stress actively suppresses hepatic molecular identity in damaged liver - CNRS - Centre national de la recherche scientifique Accéder directement au contenu
Article Dans Une Revue Molecular Systems Biology Année : 2020

Endoplasmic reticulum stress actively suppresses hepatic molecular identity in damaged liver

Résumé

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.
Fichier principal
Vignette du fichier
MSB-19-9156RR_Merged_PDF.pdf (4.18 Mo) Télécharger le fichier
2020_04_09_Appendix.pdf (8.18 Mo) Télécharger le fichier
Origine : Fichiers produits par l'(les) auteur(s)
Loading...

Dates et versions

inserm-02617039 , version 1 (25-05-2020)

Identifiants

Citer

Vanessa Dubois, Celine Gheeraert, Wouter Vankrunkelsven, Julie Dubois‐chevalier, Hélène Dehondt, et al.. Endoplasmic reticulum stress actively suppresses hepatic molecular identity in damaged liver. Molecular Systems Biology, 2020, 16 (5), pp.e9156. ⟨10.15252/msb.20199156⟩. ⟨inserm-02617039⟩
72 Consultations
128 Téléchargements

Altmetric

Partager

Gmail Facebook X LinkedIn More