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

doi:10.15252/msb.20199156

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^*

^*Corresponding author for this work

Research output: Contribution to Journal › Article › Academic › peer-review

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 language	English
Article number	e9156
Journal	Molecular Systems Biology
Volume	16
Issue number	5
DOIs	https://doi.org/10.15252/msb.20199156
Publication status	Published - 1 May 2020

Funding

The authors acknowledge O. Molendi-Coste, A. Grenon, F. Firmin, C. Mazuy, X. Mar?chal, A. Berthier, D. Sanchez-Lopez, O. Briand, B. Derudas, J. Vandel, L. L'homme (INSERM U1011, Lille, France), Lieselotte Thoolen (Amsterdam Animal Research Center, VU University Amsterdam, The Netherlands), and Shwu-Yuan Wu (University of Texas Southwestern Medical Center, Dallas, USA) for technical assistance and J. Dubois for administrative support. The authors also thank Lei Yin (University of Michigan Medical School, USA), L. Dubuquoy (INSERM U995, Lille, France), and Lies Langouche (KU Leuven, Belgium) for helpful discussions. This work was supported by grants from the Fondation pour la Recherche M?dicale (Equipe labellis?e, DEQ20150331724), ?European Genomic Institute for Diabetes? (E.G.I.D., ANR-10-LABX-46) and European Commission. B.S. is supported by the European Research Council (ERC Grant Immunobile, contract 694717). C-M.C. is supported by US National Institutes of Health (NIH 1RO1CA251698-01), Cancer Prevention & Research Institute of Texas (CPRIT RP180349 and RP190077), and Welch Foundation (I-1805).

Funders	Funder number
National Institutes of Health
National Cancer Institute	R01CA251698
Welch Foundation	I‐1805
Cancer Prevention and Research Institute of Texas	RP180349, RP190077
University of Texas Southwestern Medical Center
Medical School, University of Michigan	U995
European Commission
European Research Council	694717
Institut national de la santé et de la recherche médicale	U1011
Vrije Universiteit Amsterdam
Fondation pour la Recherche Médicale	DEQ20150331724, ANR‐10‐LABX‐46

Keywords

liver injury
NFIL3
PAR-bZIP
sepsis
super-enhancer

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.15252/msb.20199156

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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), Article e9156. https://doi.org/10.15252/msb.20199156

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title = "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 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.",

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Dubois, V, Gheeraert, C, Vankrunkelsven, W, Dubois-Chevalier, J, Dehondt, H, Bobowski-Gerard, M, Vinod, M, Zummo, FP, Güiza, F, Ploton, M, Dorchies, E, Pineau, L, Boulinguiez, A, Vallez, E, Woitrain, E, Baugé, E, Lalloyer, F, Duhem, C, Rabhi, N, van Kesteren, RE, Chiang, CM, Lancel, S, Duez, H, Annicotte, JS, Paumelle, R, Vanhorebeek, I, Van den Berghe, G, Staels, B, Lefebvre, P & Eeckhoute, J 2020, 'Endoplasmic reticulum stress actively suppresses hepatic molecular identity in damaged liver', Molecular Systems Biology, vol. 16, no. 5, e9156. https://doi.org/10.15252/msb.20199156

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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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JO - Molecular Systems Biology

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ER -

Endoplasmic reticulum stress actively suppresses hepatic molecular identity in damaged liver

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Keywords

UN SDGs

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