Séminaire d' Aranyi Tamas

Invité par Ludovic Martin

Le 5 juin 2015

Un séminaire sera donné par Aranyi Tamas, BNMI - UMR Inserm 1083 - UMR CNRS 6214.

Les étudiants souhaitant assister à la conférence doivent s'inscrire au préalable avant le Jeudi 04 juin à 12h00 dans la limite des places disponibles (inscription) (secr-inserm-angers @ contact.univ-angers.fr) en communiquant leur numéro de carte étudiante.

Pour que la participation au séminaire soit validante, il est impératif que les étudiants émargent la feuille de présence.

Pour rappel, les étudiants non inscrits ne seront pas acceptés.

12h00 - 13h00
CHU Angers - Bâtiment IBS-IRIS – Salle de conférence RDC

 secr-inserm-angers@contact.univ-angers.fr

Loss-of-fubction mutations of the ABCC6 gene lead to the development of Pseudoxanthoma elasticum (PXE) and Generalized Arterial Calcification in Infancy (GACI). Several other genetic diseases lead also to similar clinical entities and might be considered as phenocopies of PXE. Another interesting aspect of this recessive disorder is the subclinical phenotype of mutation carriers.

Although ABCC6 is mainly expressed in the liver the disease has dermatologic, ocular and cardiovascular symptoms. The severity of the symptoms is highly variable between patients. We have investigated the transcriptional regulation of the gene. We have mapped the binding of CCAAT/Enhancer binding protein ß (C/EBPß) and the conserved hepatocyte nuclear factor 4 (HNF4). Short-term activation of the ERK1/2 cascade leads to decreased HNF4 binding on ABCC6. We also observed similar decrease of HNF4 binding genome-wide in ChIP-Seq experiments. Furthermore, in accordance with transcription factor binding alterations, we have observed changes in the pattern of histone modifications. We have proved that HNF4 is directly phosphorylated by ERK1/2 in vitro at several sites. The effect of phosphomimetic HNF4 mutants was also investigated by luciferase reporter gene assays. Our results suggest that ERK1/2 activity contributes to HNF4 metabolic balance in hepatocytes. We consider that metabolic status of the patients contributes to the PXE-associated phenotypes.