Résumés disponibles (91) :

MAZUY Claire (INSERM U1011 éq. 04 - Audrey HELLEBOID-CHAPMAN)
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@mail :  claire.mazuy@inserm.fr      tél. :  0320974218


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Titre de la communication :
Crosstalk between the nuclear receptor FXR and the transcription factor FOXA2 in the liver
Auteurs (et leurs adresses) de la communication :
Mazuy C, Gheeraert C, Eeckhoute J, Chevalier-Dubois J, Staels B, Lefebvre P and Helleboid-Chapman A INSERM UMR1011 Université Lille2 Institut Pasteur de Lille EGID
Résumé de la communication :
Liver plays a key role in maintaining metabolic homeostasis. Indeed, this organ regulates carbohydrate, lipid, bile acid and amino acid metabolism and is also responsible for biotransformation and defense against xenobiotics. Consequently, understanding liver physiology is of major interest regarding the pathophysiological consequences of liver defect, including obesity-related disorders like NAFLD, diabetes and dyslipidemia. Among major regulators of liver function, FXR, a nuclear receptor activated by bile acids and highly expressed in the liver, regulates bile acid, lipid and glucose homeostasis. Like other nuclear receptors, FXR transcriptional activity is regulated by its own expression level, post-translational modifications and cofactors interactions. Preliminary analysis of genomic data from the ENCODE project revealed that the transcription factor FOXA2 is markedly colocalized with FXR in the HepG2 cell line. Beside its documented transcription factor activity, FOXA2 is known to act as “pioneer” transcription factor capable of modifying chromatin structure, favoring or preventing the binding of other transcription factors or nuclear receptors to chromatin. In addition, FOXA2 and FXR regulate similar metabolic pathways in the liver. Considering their functional and physical proximity, we postulated that FOXA2 could modulate FXR transcriptional activity.
Using genome-wide CHIP-seq approaches, we confirmed that FXR and FOXA2 are colocalized in the genome of HepG2 cells, and extended this conclusion to mouse liver. FXR and FOXA2 interacted physically as shown by co-immunoprecipitation and GST-pulldown assay near genes implicated in bile acid, glucose and lipoprotein homeostasis. Furthermore, we demonstrated that FOXA2 represses FXR transcriptional activity in HepG2 cells through transcriptomic analysis of FoxA2-depleted HepG2 cells.
This study provides the first evidence of a negative crosstalk and interaction between FOXA2 and FXR in regulating gene transcription in human hepatic cell line HepG2. The aim of this study would be to decipher the physiological consequences of this negative FXR-FOXA2 crosstalk.

MAZUY Claire (INSERM U1011 éq. 04 - Audrey HELLEBOID-CHAPMAN)