β-cell dedifferentiation is associated with epithelial-mesenchymal transition triggered by miR-7-mediated repression of mSwi/Snf complex

β-cell dedifferentiation has been revealed as a pathological mechanism underlying pancreatic dysfunction in diabetes. However, little is known on the genetic and epigenetic changes linked with the dedifferentiation of β-cells. We now report that β-cell dedifferentiation is associated with epithelial to mesenchymal transition (EMT) triggered by miR-7-mediated repression of Smarca4/Brg1 expression, a catalytic subunit of the mSwi/Snf chromatin remodeling complexes essential for β-cell transcription factors (β-TFs) activity. miR-7-mediated repression of Brg1 expression in diabetes causes an overall compaction of chromatin structure preventing β-TFs from accessing and transactivating genes maintaining the functional and epithelial identity of β-cells. Concomitantly, loss of β-cell identity impairs the ability of β-TFs Pdx1, Nkx6-1, Neurod1 to repress non-β-cell genes enriched selectively in mesenchymal cells leading to EMT, change in islet microenvironment, and fibrosis. Remarkably, anti-EMT agents normalized glucose tolerance of diabetic mice, thus revealing mesenchymal reprogramming of β-cells as a novel therapeutic target in diabetes. This study sheds light on the genetic signature of dedifferentiated β-cells and highlights how loss of mSwi/Snf activity in diabetes initiating a step-wise remodeling of epigenetic landscapes of β-cells leading to the induction of an EMT process reminiscent of a response to tissue injury.