Epigenomic plasticity enables human pancreatic α to β cell reprogramming

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

Research output: Contribution to journalArticle

211 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1275-1284
Number of pages10
JournalJournal of Clinical Investigation
Volume123
Issue number3
DOIs
StatePublished - Mar 1 2013

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Epigenomics
Islets of Langerhans
Glucagon
Histone Code
Glucagon-Secreting Cells
Insulin
Genes
RNA Sequence Analysis
Insulin-Secreting Cells
Cellular Reprogramming
Histones
Methylation
Blood Glucose

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Bramswig, N. C., Everett, L. J., Schug, J., Dorrell, C., Liu, C., Luo, Y., ... Kaestner, K. H. (2013). Epigenomic plasticity enables human pancreatic α to β cell reprogramming. Journal of Clinical Investigation, 123(3), 1275-1284. https://doi.org/10.1172/JCI66514

Epigenomic plasticity enables human pancreatic α to β cell reprogramming. / Bramswig, Nuria C.; Everett, Logan J.; Schug, Jonathan; Dorrell, Craig; Liu, Chengyang; Luo, Yanping; Streeter, Philip; Naji, Ali; Grompe, Markus; Kaestner, Klaus H.

In: Journal of Clinical Investigation, Vol. 123, No. 3, 01.03.2013, p. 1275-1284.

Research output: Contribution to journalArticle

Bramswig, NC, Everett, LJ, Schug, J, Dorrell, C, Liu, C, Luo, Y, Streeter, P, Naji, A, Grompe, M & Kaestner, KH 2013, 'Epigenomic plasticity enables human pancreatic α to β cell reprogramming', Journal of Clinical Investigation, vol. 123, no. 3, pp. 1275-1284. https://doi.org/10.1172/JCI66514
Bramswig NC, Everett LJ, Schug J, Dorrell C, Liu C, Luo Y et al. Epigenomic plasticity enables human pancreatic α to β cell reprogramming. Journal of Clinical Investigation. 2013 Mar 1;123(3):1275-1284. https://doi.org/10.1172/JCI66514
Bramswig, Nuria C. ; Everett, Logan J. ; Schug, Jonathan ; Dorrell, Craig ; Liu, Chengyang ; Luo, Yanping ; Streeter, Philip ; Naji, Ali ; Grompe, Markus ; Kaestner, Klaus H. / Epigenomic plasticity enables human pancreatic α to β cell reprogramming. In: Journal of Clinical Investigation. 2013 ; Vol. 123, No. 3. pp. 1275-1284.
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