title: Epigenomic plasticity enables human pancreatic α to β cell reprogramming.
abstract: Insulin-secreting β cells and glucagon-secreting α 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 α, β, and exocrine cells. We found that, compared with exocrine and β cells, differentiated α cells exhibited many more genes bivalently marked by the activating H3K4me3 and repressing H3K27me3 histone modifications. This was particularly true for β cell signature genes involved in transcriptional regulation. Remarkably, thousands of these genes were in a monovalent state in β cells, carrying only the activating or repressing mark. Our epigenomic findings suggested that α to β 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.
authors: Department of Genetics and Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors: Nuria C
authors: NC
authors: Bramswig
authors: Logan J
authors: LJ
authors: Everett
authors: Jonathan
authors: J
authors: Schug
authors: Craig
authors: C
authors: Dorrell
authors: Chengyang
authors: C
authors: Liu
authors: Yanping
authors: Y
authors: Luo
authors: Philip R
authors: PR
authors: Streeter
authors: Ali
authors: A
authors: Naji
authors: Markus
authors: M
authors: Grompe
authors: Klaus H
authors: KH
authors: Kaestner
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002469:Cell Separation; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D044127:Epigenesis, Genetic; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D050416:Glucagon-Secreting Cells / Q000378:metabolism / Q000502:physiology*; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000037:antagonists & inhibitors / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D050417:Insulin-Secreting Cells / Q000378:metabolism / Q000502:physiology*; D008745:Methylation; D051379:Mice; D058977:Molecular Sequence Annotation; D011499:Protein Processing, Post-Translational; D017423:Sequence Analysis, RNA; D059467:Transcriptome
chemical_list: D004791:Enzyme Inhibitors; D006657:Histones; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase