DS0403 - Exploration des systèmes et organes leur fonctionnement normal et pathologique : physiologie, physiopathologie, vieillissement

Control of normal and dysfunctional metabolic gene expression by the HNF4A-TAF4 axis. – DYSMETAF

Submission summary

Nuclear receptor HNF4A regulates metabolism through control of gene expression in liver, intestine and pancreatic ß-cells. HNF4A plays a critical role in the development and/or homeostasis of these tissues. In addition, mutations in the HNF4A coding sequence cause maturity onset of diabetes in the young (MODY1) presumably by affecting its interactions with partner proteins in an as yet poorly defined manner. We have shown that physical and functional interactions between the TAF4-TAF12 subunits of general transcription factor TFIID and the ligand binding domain of HNF4A are essential for activation of liver metabolism genes in neonatal mice. We propose a project integrating biochemical and structural approaches with state of the art mouse genetics to investigate the HNF4A-TAF4-TAF12 axis in regulating metabolism through their actions on gene expression and homeostasis in pancreatic ß-cells and the intestinal epithelium. We will use biochemical and structural approaches to characterise HNF4A-TAF4-TAF12 interactions and determine if and how they can be modulated by mutations in HNF4A that are associated with MODY1 and/or by synthetic HNF4A agonists or antagonists. We will use somatic mutagenesis to inactivate TAF4 in adult ß-cells in the embryonic and adult intestine epithelium. The effect of TAF4 loss will be evaluated by histological, molecular and functional/metabolic analyses. The structural and interaction data obtained on the HNF4A-TAF4-TAF12 complex will be exploited to generate mice expressing TAF4 mutants integrating TFIID, but compromised for their interaction with HNF4A. We will specifically test whether modulating the interaction between HNF4A and the general transcription machinery results in changes in metabolic gene expression in liver, intestine epithelium or ß-cells that in turn induce metabolic dysfunctions in the animal. Given our experience and resources, we are in a unique position to integrate the biochemical, structural and mouse genetics approaches to provide an integrative view of the HNF4A-TAF4-TAF12 axis in metabolic gene expression.

Project coordination

Irwin DAVIDSON (INSTITUT DE GENETIQUE ET DE BIOLOGIE MOLECULAIRE ET CELLULAIRE)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

IGBMC INSTITUT DE GENETIQUE ET DE BIOLOGIE MOLECULAIRE ET CELLULAIRE
IGBMC INSTITUT DE GENETIQUE ET DE BIOLOGIE MOLECULAIRE ET CELLULAIRE
INSERM INSERM Unit 1113

Help of the ANR 616,000 euros
Beginning and duration of the scientific project: September 2015 - 48 Months

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