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DNA methylation directs functional maturation of pancreatic ? cells.


ABSTRACT: Pancreatic ? 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. ? 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, ? 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 ? cell-specific Dnmt3a deletion. Furthermore, DNA methylation-mediated repression of glucose-secretion decoupling genes to modulate GSIS was conserved in human ? cells. Together, our results reveal a role for DNA methylation to direct the acquisition of pancreatic ? cell function.

SUBMITTER: Dhawan S 

PROVIDER: S-EPMC4563682 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

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DNA methylation directs functional maturation of pancreatic β cells.

Dhawan Sangeeta S   Tschen Shuen-Ing SI   Zeng Chun C   Guo Tingxia T   Hebrok Matthias M   Matveyenko Aleksey A   Bhushan Anil A  

The Journal of clinical investigation 20150622 7


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 coup  ...[more]

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