Epigenomic plasticity enables human pancreatic α to β cell reprogramming.

Bramswig NC, Everett LJ, Schug J, Dorrell C, Liu C, Luo Y, Streeter PR, Naji A, Grompe M, Kaestner KH
J Clin Invest. 2013 123 (3): 1275-84

PMID: 23434589 · PMCID: PMC3582140 · DOI:10.1172/JCI66514

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.

MeSH Terms (20)

Animals Cell Differentiation Cells, Cultured Cell Separation Enzyme Inhibitors Epigenesis, Genetic Flow Cytometry Gene Expression Profiling Glucagon-Secreting Cells Histone-Lysine N-Methyltransferase Histone Methyltransferases Histones Humans Insulin-Secreting Cells Methylation Mice Molecular Sequence Annotation Protein Processing, Post-Translational Sequence Analysis, RNA Transcriptome

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