β-Cell-Specific E2f1 Deficiency Impairs Glucose Homeostasis, β-Cell Identity, and Insulin Secretion

• Published in: Diabetes (New York, N.Y.) Vol. 72; no. 8; pp. 1112 - 1126
• Main Authors: Oger, Frédérik, Bourouh, Cyril, Friano, Marika Elsa, Courty, Emilie, Rolland, Laure, Gromada, Xavier, Moreno, Maeva, Carney, Charlène, Rabhi, Nabil, Durand, Emmanuelle, Amanzougarene, Souhila, Berberian, Lionel, Derhourhi, Mehdi, Blanc, Etienne, Hannou, Sarah Anissa, Denechaud, Pierre-Damien, Benfodda, Zohra, Meffre, Patrick, Fajas, Lluis, Kerr-Conte, Julie, Pattou, François, Froguel, Philippe, Pourcet, Benoit, Bonnefond, Amélie, Collombat, Patrick, Annicotte, Jean-Sébastien
• Format: Journal Article
• Language: English
• Published: United States American Diabetes Association 01.08.2023
• Subjects: Animals; Beta cells; Biochemistry, Molecular Biology; Chromatin; Chromatin - metabolism; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 2 - genetics; Diabetes Mellitus, Type 2 - metabolism; Down-regulation; E2F1 protein; Endocrinology and metabolism; Glucose; Glucose - metabolism; Glucose tolerance; Histones; Histones - metabolism; Homeostasis; Homeostasis - genetics; Human health and pathology; Humans; Insulin; Insulin - metabolism; Insulin Secretion; Insulin-Secreting Cells - metabolism; Intolerance; Life Sciences; Mice; Mice, Knockout; Molecular modelling; Pharmaceutical sciences; Pharmacology; Promoters; Secretion; Type 2 diabetes; Cell-cycle regulator and transcription factor E2F1; Pancreatic β-cell; Insulin secretion
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/db22-0604

The loss of pancreatic β-cell identity has emerged 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, altered endocrine cell mass, downregulation of many β-cell genes, and concomitant increase of non-β-cell markers. Mechanistically, epigenomic profiling of the 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 sustained control of β-cell and non-β-cell transcriptional programs. β-Cell-specific E2f1 deficiency in mice impairs glucose tolerance. Loss of E2f1 function alters the ratio of α- to β-cells but does not trigger β-cell conversion into α-cells. Pharmacological inhibition of E2F activity inhibits glucose-stimulated insulin secretion and alters β- and α-cell gene expression in human islets. E2F1 maintains β-cell function and identity through control of transcriptomic and epigenetic programs.