Pancreatic β-cell specific loss of E2f1 impairs insulin secretion and β-cell identity through the epigenetic repression of non β-cell programs

Abstract

The loss of pancreatic {beta}-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 {beta}-cell identity and insulin secretion. We show that the {beta}-cell-specific loss of E2f1 function in mice triggers glucose intolerance associated with defective insulin secretion, an altered -to-{beta}-cell ratio, a downregulation of many {beta}-cell genes and a concomitant increase of non-{beta}-cell markers. Mechanistically, the epigenomic profiling of non-beta cell upregulated gene promoters identified an enrichment of bivalent H3K4me3/H3K27me3 or H3K27me3 marks. Conversely, downregulated genes were enriched in active chromatin H3K4me3 and H3K27ac histone marks. We find that histone deacetylase inhibitors modulate E2F1 transcriptional and epigenomic signatures associated with these {beta}-cell dysfunctions. Finally, the pharmacological inhibition of E2F transcriptional activity in human islets also impairs insulin secretion and the expression of {beta}-cell identity genes. Our data suggest that E2F1 is critical for maintaining {beta}-cell identity through a sustained repression of non {beta}-cell transcriptional programs.