Epigenomic plasticity enables human pancreatic α to β cell reprogramming

Insulin-secreting beta cells and glucagon-secreting alpha cells maintain physiological blood glucose levels, and their malfunction drives diabetes development. Using ChIP sequencing and RNA sequencing analysis, we determined the epigenetic and transcriptional landscape of human pancreatic alpha, beta, and exocrine cells. We found that, compared with exocrine and beta cells, differentiated alpha cells exhibited many more genes bivalently marked by the activating H3K4me3 and repressing H3K27me3 histone modifications. This was particularly true for beta cell signature genes involved in transcriptional regulation. Remarkably, thousands of these genes were in a monovalent state in beta cells, carrying only the activating or repressing mark. Our epigenomic findings suggested that alpha to beta cell reprogramming could be promoted by manipulating the histone methylation signature of human pancreatic islets. Indeed, we show that treatment of cultured pancreatic islets with a histone methyltransferase inhibitor leads to colocalization of both glucagon and insulin and glucagon and insulin promoter factor 1 (PDX1) in human islets and colocalization of both glucagon and insulin in mouse islets. Thus, mammalian pancreatic islet cells display cell-type-specific epigenomic plasticity, suggesting that epigenomic manipulation could provide a path to cell reprogramming and novel cell replacement-based therapies for diabetes.