Epigenomic plasticity enables human pancreatic α to β cell reprogramming
Nuria C. Bramswig, … , Markus Grompe, Klaus H. Kaestner
Nuria C. Bramswig, … , Markus Grompe, Klaus H. Kaestner
Published February 22, 2013
Citation Information: J Clin Invest. 2013;123(3):1275-1284. https://doi.org/10.1172/JCI66514.
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Research Article

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

Nuria C. Bramswig, Logan J. Everett, Jonathan Schug, Craig Dorrell, Chengyang Liu, Yanping Luo, Philip R. Streeter, Ali Naji, Markus Grompe, Klaus H. Kaestner

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Figure 6

Inhibition of histone methyltransferases leads to partial endocrine cell-fate conversion.

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Inhibition of histone methyltransferases leads to partial endocrine cell...
(A) H3K27me3 ChIP-Seq analysis of human islets shows decreased H3K27me3 levels at the ARX, MAFA, and PDX1 loci following treatment of human islets with the histone methyltransferase inhibitor Adox. (B) Adox-treatment of human islets results in colocalization of glucagon (red) and insulin (green) granules within the same cell (yellow arrows), suggesting partial endocrine cell fate conversion, which was not seen in vehicle-treated islets (control). Original magnification, ×63. For Z-stack confocal images see Supplemental Videos 1 and 2. (C) Treatment of human islets with Adox results in colocalization of the β cell–specific transcription factor Pdx1 (white) and glucagon (red), further indicating endocrine reprogramming (white arrows: glucagon-positive, Pdx1-negative cells; yellow arrows: glucagon-positive, Pdx1-positive cells). The images on the right correspond to the area within yellow box. Original magnification, ×63. (D) Quantification of glucagon-positive, Pdx1-positive cells in untreated and Adox-treated human islets reveals many double-positive cells after Adox treatment, indicating initiation of reprogramming events in α cells. (E) Adox treatment of human islets leads to a decrease in NKX6-1 and MAFA levels in β cells (n = 3 α, n = 3 β, n = 2 treated α, n = 2 treated β), an increase in PDX1-levels, and no change in INS and GCG levels. (F) In Adox-treated α cells, we observe no change in INS and GCG expression, a slight decrease in NKX6-1 and MAFA levels, and an increase of ARX and PDX1 expression.