m6A mRNA methylation regulates human β-cell biology in physiological states and in type 2 diabetes
m6A mRNA methylation regulates human β-cell biology in physiological states and in type 2 diabetes
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DOI：
10.1038/s42255-019-0089-9
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发表时间：
2019-08-01
影响因子：
20.8
通讯作者：
Kulkarni, Rohit N.
中科院分区：
文献类型：
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作者：
De Jesus, Dario F.;Zhang, Zijie;Kulkarni, Rohit N.
胰岛细胞生物学的调节对葡萄糖稳态至关重要(1)。N-6-甲基腺苷(m(6)A)是哺乳动物体内含量最丰富的内部信使RNA(m(6)A)修饰。在这里，我们报告了m(6)A图谱将人类2型糖尿病(T2D)胰岛与对照分离得明显好于转录组，并且m(6)A对于β细胞生物学至关重要。M(6)人T2D胰岛的测序揭示了几个低甲基化转录本，它们与细胞周期进展、胰岛素分泌和胰岛素/IGF1-AKT-PDX1途径有关。Endo-beta H1细胞中m(6)A水平的缺失会导致细胞周期停滞，并通过降低AKT磷酸化和PDX1蛋白水平来削弱胰岛素分泌。表现出m(6)A水平降低的β细胞特异性Mettl14基因敲除小鼠，模拟了人类T2D的胰岛表型，由于β细胞增殖减少和胰岛素脱颗粒而导致早期糖尿病发作和死亡。我们的数据强调了RNA甲基化在调节人类β细胞生物学中的重要性，并为潜在的以m(6)A调节剂为靶向的治疗提供了理论基础，以保护糖尿病中的β细胞存活和功能。
The regulation of islet cell biology is critical for glucose homeostasis(1). N-6-methyladenosine (m(6)A) is the most abundant internal messenger RNA (mRNA) modification in mammals(2). Here, we report that the m(6)A landscape segregates human type 2 diabetes (T2D) islets from controls significantly better than the transcriptome and that m(6)A is vital for beta-cell biology. m(6)A sequencing in human T2D islets reveals several hypomethylated transcripts that are involved in cell-cycle progression, insulin secretion, and the insulin/IGF1-AKT-PDX1 pathway. Depletion of m(6)A levels in EndoC-beta H1 cells induces cell-cycle arrest and impairs insulin secretion by decreasing AKT phosphorylation and PDX1 protein levels. beta-cell-specific Mettl14 knockout mice, which display reduced m(6)A levels, mimic the islet phenotype in human T2D with early diabetes onset and mortality owing to decreased beta-cell proliferation and insulin degranulation. Our data underscore the significance of RNA methylation in regulating human beta-cell biology, and provide a rationale for potential therapeutic targeting of m(6)A modulators to preserve beta-cell survival and function in diabetes.