Theme 4: Integrated transcriptional analysis of liver diseases

Liver diseases are a major burden on human health. In particular, modern lifestyles, including excessive food and alcohol consumptions, are responsible for an ever-increasing number of liver failures and cancers.

Liver diseases are caused by alterations in the activities of hepatocytes, the main cell type that makes up this organ. Indeed, a dysfunctional liver is characterized by unhealthy hepatocytes, unable to maintain normal homeostatic functions. Alterations to hepatocyte functions are accompanied by changes in the activities of other liver cell types, including hepatic stellate cells (HSCs). Indeed, HSCs are able to adopt a myofibroblastic phenotype that is responsible for the development of fibrosis, an advanced stage of chronic liver diseases characterized by an alteration of the extracellular matrix surrounding hepatocytes.

Our team studies the molecular mechanisms at play in diseased livers that underlie alterations in hepatocyte and HSC activities. Specifically, we investigate how alterations in gene expression occur in these cells and whether these can be corrected to restore normal cellular functions. Finally, given that liver cells communicate directly with each other, we are also studying how changes in gene expression translate into changes in the intercellular dialogue in diseased livers.

Through our work, we hope to contribute to a better understanding of the molecular mechanisms underlying alterations to liver functions with the aim to identify potential new strategies to treat liver diseases.

Philippe LEFEBVRE
DR1 Inserm, responsable d’équipe
Numéro ORCID : 0000-0002-9366-5129

Philippe Lefebvre completed his PhD in Biochemistry at ULille1 in 1988, during which he studied the mechanism of action of anti-glucocorticoids under the supervision of Pr P. Formstecher. He then did his postdoctoral training in Dr G.L. Hager’s lab at N.I.H., N.C.I., Bethesda to study transcriptional mechanisms governing the glucocorticoid-driven, cell type-specific expression of the Mouse Mammary Tumor Virus (MMTV) and chromatin-regulated processes. Since 1992, he has been at INSERM in Lille where he is currently a research director. He first established a research group working mostly on nuclear retinoic acid receptors (RARs, RXRs) and orphan receptors structure and regulation (Nurr1, Nur77) in cellular differentiation and cancer. His scientific interests then switched towards the study of the role of nuclear receptors in cardiometabolic diseases, mostly focusing on PPARα and FXR.  He now leads a research group in Pr Bart Staels laboratory and, together with Dr Jérôme Eeckhoute, focuses mostly on nuclear receptor-regulated molecular mechanisms governing liver pathophysiology, with a specific emphasis on NASH and fibrosis.

Jérôme EECKHOUTE
DR2 CNRS
Numéro ORCID : 0000-0002-7222-9264

Jérôme Eeckhoute earned his PhD in molecular biology from the University of Lille in 2003 owing to studies defining the functional consequences of diabetes-associated mutations of the nuclear receptor HNF4A. He subsequently moved to the Dana-Farber cancer institute (Harvard Medical School, Boston, USA) where he was involved in defining the transcription factor hierarchy and interplay with chromatin involved in regulatory activities of the estrogen receptor. Ever since his recruitment by the CNRS in 2008, he has been focusing on applying functional genomics to decipher molecular mechanisms involved in (dys)regulation of cell/tissue-specific transcriptional regulatory programs with a special emphasis on nuclear receptors and chromatin/epigenomics. Recent interests lie in the characterization of molecular entities and mechanisms responsible for establishment and maintenance/loss of cell identity in liver pathophysiology.

Viktorija AVILKINA

Post-doc

Alexandre BERTHIER
Post-doc

Numéro ORCID : 0000-0003-4153-4810

Alexandre Berthier obtained his PhD in life sciences (molecular biology) at the University of Besançon in 2008 where he developed "biosensors/cellular model" tools for the identification of ligands of the estrogen receptor (ERα) and the study of DNA/protein and protein/protein interactions. He then joined the group of Prof. Uwe Schlattner (University of Grenoble) to study the AMP-regulated kinase (AMPK). In November 2010, he joined the team led by Dr. Philippe Lefebvre to conduct research on circadian variations in the hepatic activities of the nuclear receptors FXR, PPARα and REV-ERBα.

Clémence BOULET
IE

Numéro ORCID : 0000-0002-2866-0372

Clémence Boulet obtained her Master's degree in Biology and Health at the University of Lille in 2019, thanks to her participation the study of transcription factors involved in hepatic stellate cell activation in liver fibrosis, under the supervision of Dr J. Eeckhoute. Since then, she has been working in our team as a research engineer being involved in several projects dedicated to dissection of molecular pathways controlling the phenotype of stellate cells and hepatocytes in liver pathophysiology. Her involvement in various projects has enabled her to develop skills in molecular biology, cell biology, biochemistry and immunohistology.

Julie CHEVALIER
IR Inserm
Numéro ORCID : 0000-0003-0471-752X

Hélène DEHONDT
IE Univ Lille
Numéro ORCID : 0000-0003-2900-4673

Céline GHEERAERT
IE Univ Lille
Numéro ORCID : 0000-0003-b-6363

Loïc GUILLE

IE

Numéro ORCID : 0000-0002-8387-1092

Florian Huglo

Master 2

Georgiana TOMA

Post-doc

Ludivine VASSEUR

Doctorante

Numéro ORCID : 0000-0001-5122-1717

Ninon VERY
Post-doc

Manjula VINOD
Post-doc

Rebecca YOUSSEF

Doctorante

Numéro ORCID : 0009-0002-8442-4224

Rebecca Youssef is a PhD student in biology at the University of Lille. She is currently conducting research on sex-dependent transcriptional regulation in the liver.

Recent work by our team has :

- characterize a sex-dependent transcriptional signature that reflects the evolutionary stages of non-alcoholic fatty liver disease (Vandel et al. Hepatology. 2020).

- Define how the transcriptional program controlling hepatocyte identity is disrupted by endoplasmic reticulum stress during liver injury (Dubois V et al. Mol Syst Biol 2020).

- Identify the BNC2 transcription factor as a key player in establishing the myofibroblast transcriptional program involved in the development of hepatic fibrosis (Bobowski-Gerard M et al. Nat Commun, 2022).

Translated with www.DeepL.com/Translator (free version)

Institut Pasteur de Lille ; Univ Lille ; Inserm ; Fondation recherche médicale ;

Agence Nationale de la Recherche (ANR) ;

MEL; European Genomics Institute for Diabetes (E.G.I.D); European Commission ; Région Hauts-de-France

Bobowski-Gerard M, Boulet C, Zummo PF, Dubois-Chevalier J, Gheeraert C, Bou Saleh M, Strub J-M, Farce A, Ploton M, Guille L, Vandel J, Bongiovanni A, Very N, Woitrain E, Deprince A, Lalloyer F, Bauge E, Ferri L, Ntandja-Wandji L-C, Cotte KA, Grangette C, Vallez E, Cianférani S, Raverdy V, Caiazzo R, Gnemmi V, Leteurtre E, Pourcet B, Paumelle R, Ravnskjaer K, Lassailly G, Haas TJ, Mathurin P, Pattou F, Dubuquoy L, Staels B, Lefebvre P, Eeckhoute J

Functional genomics uncovers the transcription factor BNC2 as required for myofibroblastic activation in fibrosis.

Nat Commun, 2022 Sep 10;13(1):5324.

Vinod M, Berthier A, Maréchal X, Gheeraert C, Boutry R, Delhaye S, Annicotte J-S, Duez H, Hovasse A, Cianférani S, Montaigne D, Eeckhoute J, Staels B, Lefebvre P

Timed use of digoxin prevents heart ischemia–reperfusion injury through a REV-ERBα–UPS signaling pathway

Nature Cardiovascular Research, 2022

Vandel J, Dubois-Chevalier J, Gheeraert C, Derudas B, Raverdy V, Thuillier D, Van Gaal L, Francque S, Pattou F, Staels B, Eeckhoute J, Lefebvre P.

Hepatic molecular signatures highlight the Non-Alcoholic SteatoHepatitis (NASH) sexual dimorphism.

Hepatology. 2020 Mar;73(3):920-936. doi: 10.1002/hep.31312

Ploton M, Mazuy C, Gheeraert C, Dubois V, Berthier A, Dubois-Chevalier J, Maréchal X, Bantubungi-Blum K, Diemer H, Cianférani S, Strub JM, Helleboid-Chapman A, Eeckhoute J, Staels B, Lefebvre P.

The Nuclear Bile Acid Receptor FXR is a PKA- and FOXA2-Sensitive Activator of Fasting Hepatic Gluconeogenesis.

J Hepatol. 2018 Jul 4. pii: S0168-8278(18)32175-5.

Berthier A, Vinod M, Porez G, Steenackers A, Alexandre J, Yamakawa N, Gheeraert C, Ploton M, Maréchal X, Dubois-Chevalier J, Hovasse A, Schaffer-Reiss C, Cianférani S, Rolando C, Bray F, Duez H, Eeckhoute J, Lefebvre T, Staels B, Lefebvre P.

Combinatorial regulation of hepatic cytoplasmic signaling and nuclear transcriptional events by the OGT/REV-ERBα complex.

Proc Natl Acad Sci U S A. 2018 Nov 5. pii: 201805397.

Lefebvre P, Lalloyer F, Baugé E, Pawlak M, Gheeraert C, Dehondt H, Vanhoutte J, Woitrain E, Hennuyer N, Mazuy C, Bobowski-Gérard M, Zummo FP, Derudas B, Driessen A, Hubens G, Vonghia L, Kwanten WJ, Michielsen P, Vanwolleghem T, Eeckhoute J, Verrijken A, Van Gaal L, Francque S, Staels B.

Interspecies NASH disease activity whole-genome profiling identifies a fibrogenic role of PPARα-regulated dermatopontin.

JCI Insight. 2017 Jul 6;2(13).

Dubois-Chevalier J, Dubois V, Dehondt H, Mazrooei P, Mazuy C, Sérandour AA, Gheeraert C, Guillaume P, Baugé E, Derudas B, Hennuyer N, Paumelle R, Marot G, Carroll JS, Lupien M, Staels B, Lefebvre P, Eeckhoute J.

The logic of transcriptional regulator recruitment architecture at cis-regulatory modules controlling liver functions.

Genome Res. 2017 Jun;27(6):985-996.

Dubois V, Eeckhoute J, Lefebvre P, Staels B.

Distinct but complementary contribution of PPAR isotypes to energy homeostasis

J Clin Invest. 2017 Apr 3;127(4):1202-1214.

D. Montaigne, X. Maréchal, T. Modine, A. Coisne, S. Mouton, G. Fayad, S. Ninni, C. Klein, S. Ortmans, C. Seunes, C. Potelle, A. Berthier, C. Gheeraert, C. Piveteau, R. Deprez, J. Eeckhoute, H. Duez, D. Lacroix, B. Deprez, B. Jegou, M. Koussa, J.L. Edmé, P. Lefebvre, B. Staels.

Day-time variation of peri-operative myocardial injury in cardiac surgery and its prevention by Rev-erbα antagonism: a single-centre propensity-matched cohort and a randomised study.

The Lancet 2017 Oct 26. pii: S0140-6736(17)32132-3.