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 cell-autonomous 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.
We thank Dr Raphael Scharfmann and members of the INSERM UMR1167 and U1283 for helpful discussions, and Céline Gheeraert for excellent help with ChIP experiments. Human islets were provided through the JDRF award 31-2008-416 (ECIT Islet for Basic Research program). The authors thank the Experimental Resources platform from Université de Lille, especially Cyrille Degraeve, Yann Lepage, Mélanie Besegher and Julien Devassine for animal care. We thank the Department of Histology from the Lille Medicine Faculty, particularly M.H. Gevaert and R.M. Siminski, for histological preparations. We thank “France Genomique” consortium (ANR-10-INSB-009). This work was supported by grants from « European Genomic Institute for Diabetes » E.G.I.D, ANR-10-LABX-46 and Equipex 2010 ANR-10-EQPX-07-01; 'LIGAN-PM' Genomics platform, a French State fund managed by the Agence Nationale de la Recherche under the frame program Investissements d’Avenir I-SITE ULNE / ANR-16-IDEX-0004 ULNE (to J.K.C., F.P., P.F., A.B. and J-S. A), Agence Nationale pour la Recherche (BETAPLASTICITY, ANR-17-CE14-0034 to P.F., P.C. and J-S. A.), European Foundation for the Study of Diabetes (EFSD, to J-S.A.), European Commission, INSERM, CNRS, Institut Pasteur de Lille (CPER CTRL Melodie, to E.C., B.P. and J-S.A.), Fondation pour la Recherche Médicale (FRM Grant EQU202103012732 to J-S.A.), Association pour la Recherche sur le Diabète (to J-S.A.), Université de Lille (to F.O., C.B., X.G., N.R. and J-S.A.), I-SITE ULNE (EpiRNAdiab Sustain grant to J-S.A.), Conseil Régional Hauts de France and Métropole Européenne de Lille (to X.G., N.R. and J-S.A.), F.E.D.E.R. (Fonds Européen de Développement Régional, to N.R., P.F. and J-S.A.) and Société Francophone du Diabète (to S.A.H. and J-S.A).