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.
View: Text | PDF
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

×

Figure 3

Human α, β, and exocrine cells exhibit convergent monovalent H3K4me3 and H3K27me3 profiles, which correlate highly with genome-wide expression data.

Options: View larger image (or click on image) Download as PowerPoint
Human α, β, and exocrine cells exhibit convergent monovalent H3K4me3 and...
(A) The majority of H3K4me3-marked genes are shared between α, β, and exocrine cells (their overlap is indicated in the purple portion of the bars, 83%–95%). (B) H3K27me3 modification patterns are similar among pancreatic cell types (73%–83%, dark blue portion of the bars). (C and D) Heat map analysis (columns, individual samples; rows, genes) confirms low interindividual variability for all H3K4me3 (C) and H3K27me3 (D) peaks identified from the pooled data (peaks called by algorithms are indicated by the solid bars on the left of the heat maps). All pairs of columns in every heat map are significantly correlated based on correlation t test assessed by R statistics software (P < 2.2 × 10–16). (E–G) Normalized expression values obtained by RNA-Seq for genes grouped by their histone modification status in each cell type are shifted significantly above or below baseline expression (Wilcoxon signed rank test, P < 2.2 × 10–16). A shift above 0 on this scale indicates highly expressed genes and was observed for gene groups marked solely by H3K4me3 in all cell types (pink boxes in E–G). A shift below 0 on this scale indicates low or nonexpressed genes and was observed in all bivalently marked gene groups (light blue boxes) and monovalently H3K27me3-marked genes (dark blue boxes) in all cell types. Therefore, the histone modification states are significantly correlated with gene expression levels.