Diabetes.: co-auth.: group Fajas

Diabetes. 2023 May 22;db220604.

 doi: 10.2337/db22-0604. Online ahead of print.

β-cell specific E2f1 deficiency impairs glucose homeostasis, β-cell identity and insulin secretion

Frédérik Oger 1Cyril Bourouh 1Marika Elsa Friano 2Emilie Courty 3Laure Rolland 3Xavier Gromada 1Maeva Moreno 1Charlène Carney 1Nabil Rabhi 4Emmanuelle Durand 1Souhila Amanzougarene 1Lionel Berberian 1Mehdi Derhourhi 1Etienne Blanc 1Sarah Anissa Hannou 1Pierre-Damien Denechaud 5Zohra Benfodda 6Patrick Meffre 6Lluis Fajas 5Julie Kerr-Conte 7François Pattou 7Philippe Froguel 1 8Benoit Pourcet 9Amélie Bonnefond 1 8Patrick Collombat 2Jean-Sébastien Annicotte 3 10

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The loss of pancreatic β-cell identity emerges as an important feature of type 2 diabetes development, but the molecular mechanisms are still elusive. Here, we explore the cellautonomous role of the cell cycle regulator and transcription factor E2F1 in the maintenance of β-cell identity, insulin secretion and glucose homeostasis. We show that the β-cell-specific loss of E2f1 function in mice triggers glucose intolerance associated with defective insulin secretion, an altered endocrine cell mass, a downregulation of many β-cell genes and a concomitant increase of non-β-cell markers. Mechanistically, the epigenomic profiling of promoters of these non-β-cell upregulated genes identified an enrichment of bivalent H3K4me3/H3K27me3 or H3K27me3 marks. Conversely, promoters of downregulated genes were enriched in active chromatin H3K4me3 and H3K27ac histone marks. We find that specific E2f1 transcriptional, cistromic and epigenomic signatures are associated with these β-cell dysfunctions, with E2F1 directly regulating several β-cell genes at the chromatin level. Finally, the pharmacological inhibition of E2F transcriptional activity in human islets also impairs insulin secretion and the expression of β-cell identity genes. Our data suggest that E2F1 is critical for maintaining β-cell identity and function through a sustained control of β-cell and non β-cell transcriptional programs.