TY - JOUR
T1 - Endoplasmic reticulum stress actively suppresses hepatic molecular identity in damaged liver
AU - Dubois, Vanessa
AU - Gheeraert, Céline
AU - Vankrunkelsven, Wouter
AU - Dubois-Chevalier, Julie
AU - Dehondt, Hélène
AU - Bobowski-Gerard, Marie
AU - Vinod, Manjula
AU - Zummo, Francesco Paolo
AU - Güiza, Fabian
AU - Ploton, Maheul
AU - Dorchies, Emilie
AU - Pineau, Laurent
AU - Boulinguiez, Alexis
AU - Vallez, Emmanuelle
AU - Woitrain, Eloise
AU - Baugé, Eric
AU - Lalloyer, Fanny
AU - Duhem, Christian
AU - Rabhi, Nabil
AU - van Kesteren, Ronald E.
AU - Chiang, Cheng Ming
AU - Lancel, Steve
AU - Duez, Hélène
AU - Annicotte, Jean Sébastien
AU - Paumelle, Réjane
AU - Vanhorebeek, Ilse
AU - Van den Berghe, Greet
AU - Staels, Bart
AU - Lefebvre, Philippe
AU - Eeckhoute, Jérôme
PY - 2020/5/1
Y1 - 2020/5/1
N2 - 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.
AB - 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.
KW - liver injury
KW - NFIL3
KW - PAR-bZIP
KW - sepsis
KW - super-enhancer
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U2 - 10.15252/msb.20199156
DO - 10.15252/msb.20199156
M3 - Article
C2 - 32407006
AN - SCOPUS:85084785057
SN - 1744-4292
VL - 16
JO - Molecular Systems Biology
JF - Molecular Systems Biology
IS - 5
M1 - e9156
ER -