DNA methylation directs functional maturation of pancreatic β cells
DNA methylation directs functional maturation of pancreatic β cells
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DOI：
10.1172/jci79956
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发表时间：
2015-07-01
影响因子：
15.9
通讯作者：
Bhushan, Anil
中科院分区：
文献类型：
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作者：
Dhawan, Sangeeta;Tschen, Shuen-Ing;Bhushan, Anil
胰岛β细胞在餐后血糖水平升高时分泌胰岛素，以防止高血糖，并在空腹条件下抑制胰岛素分泌，以防止低血糖。β细胞在出生时缺乏这种功能，并在新生儿时期获得葡萄糖刺激的胰岛素分泌(GSIS)。在这里，我们已经证明，在出生后的生命中，从头DNA甲基转移酶DNMT3A通过抑制关键基因启动代谢程序，从而使胰岛素分泌与血糖水平耦合。在小鼠模型中，DNMT3A的β细胞特异性缺失阻止了代谢转换，导致GSIS丢失。DNMT3A与编码己糖激酶1(HK1)和乳酸脱氢酶A(LDHA)的基因的启动子结合，这两个关键的DNMT3A靶标的敲除恢复了具有β细胞特异性DNMT3A缺失的动物胰岛的GSIS反应。此外，DNA甲基化介导的调节GSIS的葡萄糖分泌解偶联基因的抑制在人类β细胞中是保守的。综上所述，我们的结果揭示了DNA甲基化在指导胰岛β细胞功能获得中的作用。
Pancreatic beta 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. beta 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, beta 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 beta cell-specific Dnmt3a deletion. Furthermore, DNA methylation-mediated repression of glucose-secretion decoupling genes to modulate GSIS was conserved in human beta cells. Together, our results reveal a role for DNA methylation to direct the acquisition of pancreatic beta cell function.