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 March 1, 2013; First 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 2

Genome-wide transcriptome analysis using RNA-Seq confirms high purity of sorted cell populations and reveals cell-type–specific gene expression.

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Genome-wide transcriptome analysis using RNA-Seq confirms high purity of...
(A) Principal component analysis displays distinct cell populations and clustering of replicates (n = 3 α, n = 3 β, n = 2 exocrine), which confirms the high purity of our sorted cell populations (dots, replicates; crosses, averages). (B) Heat map analysis shows groups of genes with distinct expression patterns across cell types (columns: cell types, rows: genes). The orange, blue, and yellow bars on the left side of the heat map indicate α, β, and exocrine cell–specific gene clusters, respectively. The darker portion of these bars indicates stronger cell-type specificity of the gene cluster. We highlight important genes, including genes found to be associated with diabetes in genome-wide association studies (marked with asterisks). The complete gene lists of α, β, and exocrine cell–specific genes are provided in Supplemental Table 2.