DNA methylation directs functional maturation of pancreatic β cells

Sangeeta Dhawan, Shuen Ing Tschen, Chun Zeng, Tingxia Guo, Matthias Hebrok, Aleksey V Matveyenko, Anil Bhushan

Research output: Contribution to journalArticle

57 Scopus citations

Abstract

Pancreatic β cells secrete insulin in response to postprandial increases in glucose levels to prevent hyperglycemia and inhibit insulin secretion under fasting conditions to protect against hypoglycemia. β cells lack this functional capability at birth and acquire glucose-stimulated insulin secretion (GSIS) during neonatal life. Here, we have shown that during postnatal life, the de novo DNA methyltransferase DNMT3A initiates a metabolic program by repressing key genes, thereby enabling the coupling of insulin secretion to glucose levels. In a murine model, β cell-specific deletion of Dnmt3a prevented the metabolic switch, resulting in loss of GSIS. DNMT3A bound to the promoters of the genes encoding hexokinase 1 (HK1) and lactate dehydrogenase A (LDHA) ' both of which regulate the metabolic switch ' and knockdown of these two key DNMT3A targets restored the GSIS response in islets from animals with β cell-specific Dnmt3a deletion. Furthermore, DNA methylation- mediated repression of glucose-secretion decoupling genes to modulate GSIS was conserved in human β cells. Together, our results reveal a role for DNA methylation to direct the acquisition of pancreatic β cell function.

Original languageEnglish (US)
Pages (from-to)2851-2860
Number of pages10
JournalJournal of Clinical Investigation
Volume125
Issue number7
DOIs
StatePublished - Jul 1 2015
Externally publishedYes

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ASJC Scopus subject areas

  • Medicine(all)

Cite this

Dhawan, S., Tschen, S. I., Zeng, C., Guo, T., Hebrok, M., Matveyenko, A. V., & Bhushan, A. (2015). DNA methylation directs functional maturation of pancreatic β cells. Journal of Clinical Investigation, 125(7), 2851-2860. https://doi.org/10.1172/JCI79956