Résumés disponibles (85) :

GROMADA Xavier (UMR CNRS 8199 éq. 02 - Jean-Sebastien ANNICOTTE)
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@mail :  jean-sebastien.annicotte@inserm.fr      tél. :  0778675187


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Titre de la communication :
E2F1 controls pancreatic β-cell function and identity
Auteurs (et leurs adresses) de la communication :
Xavier Gromada, Nabil Rabhi, Philippe Froguel and Jean-Sébastien Annicotte *European Genomic Institute for Diabetes, CNRS UMR 8199, Lille 2 University, Lille, France
Résumé de la communication :
Background and aims: Dysfunction of pancreatic β cells, associated with a decrease in their number are responsible for diabetes development. In this regard, cell cycle regulators play key roles in the control of cell proliferation and cell fate. We previously reported the important role of the CDK4-pRb-E2F1 pathway, a key component of the cell cycle machinery, on glucose homeostasis, post-natal β-cell proliferation, mass and function. However, the molecular link between E2F1 and the control of endocrine cell fate or differentiation remains unknown.

Methods: To identify the potential role of E2F1 in pancreatic β-cell differentiation, we used E2f1 +/+ and -/- mice and studied the proportion of α and β cell in these genetic backgrounds. To further understand the potential role of E2F1 in maintaining β-cell identity, we used shRNA technology in MIN6 cells, transient transfection experiments, chromatin immunoprecipitation assays and E2F1 inhibitors in vitro and in vivo. Moreover to confirm the cell-autonomous function of E2f1 in β cells, we have generated a beta-cell specific inactivation of the E2f1 gene in mice. We further used human islets to demonstrate the key role of maintaining E2F1 activity for β-cell identity.

Results: We show here that E2f1 deficiency induced a β-to-α-like cell conversion, suggesting that E2f1 could be directly involved in this process. Knocking-down E2f1 in the β-cell line Min6 induced the α-cell specific transcription factor Arx at the mRNA and protein levels. We also demonstrated that E2F1, in concert with pRb, repressed Arx in β cells at the promoter level, through an epigenetic mechanism involving CpG island methylation. These results were confirmed in a E2f1 beta cell specific knock-out mouse model where the mice present glucose intolerance associated with a decrease of insulin secretion in response to glucose. Finally, inhibiting E2F1 activity in human islets induced a β-to-α-like cell conversion, suggesting an important role for E2F1 in human islets.

Conclusion: Our data demonstrate that E2f1 could be a constitutive repressor of the α-cell specifn factor Arx, crucial to maintain the cellular identity of pancreatic β cells. The underlying repressive mechanisms are still under investigations but could involve a demethylation process.

GROMADA Xavier (UMR CNRS 8199 éq. 02 - Jean-Sebastien ANNICOTTE)