The regulation of islet cell biology is critical for glucose homeostasis1. N6-methyladenosine (m6A) is the most abundant internal messenger RNA (mRNA) modification in mammals2. Here, we report that the m6A landscape segregates human type 2 diabetes (T2D) islets from controls significantly better than the transcriptome and that m6A is vital for β-cell biology. m6A 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 m6A levels in EndoC-βH1 cells induces cell-cycle arrest and impairs insulin secretion by decreasing AKT phosphorylation and PDX1 protein levels. β-cell-specific Mettl14 knockout mice, which display reduced m6A levels, mimic the islet phenotype in human T2D with early diabetes onset and mortality owing to decreased β-cell proliferation and insulin degranulation. Our data underscore the significance of RNA methylation in regulating human β-cell biology, and provide a rationale for potential therapeutic targeting of m6A modulators to preserve β-cell survival and function in diabetes.
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m6A sequencing and RNA sequencing data in human islets have been deposited with the National Center for Biotechnology Information Gene Expression Omnibus under accession code GSE120024. m6A sequencing and RNA sequencing data in EndoC-βH1 cells have been deposited under accession code GSE132306. RNA sequencing in mouse FACS-sorted β-cells have been deposited under the accession code GSE132306. Phospho-antibody microarray data performed in mouse whole islets have been deposited under the accession code GSE132111.The data that support the findings of this study are available from the corresponding author upon reasonable request. R package RADAR code is available upon request.
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The authors thank the Joslin Islet Isolation Core, Joslin Bioinformatics Core, and Joslin Advanced Microscopy Core (P30 DK36836). This work is supported by NIH grants R01 DK67536 (R.N.K.), UC4 DK116278 (R.N.K. and C.H.) and RM1 HG008935 (C.H.). R.N.K. acknowledges support from the Margaret A. Congleton Endowed Chair and C.H. is a Howard Hughes Medical Institute Investigator. M.K.G. acknowledges support from the JDRF Advanced Postdoctoral Fellowship Award 3-APF-2017-393-A-N. The authors sincerely thank the families of the human islet donors.
C.H. is a scientific founder and a member of the scientific advisory board of Accent Therapeutics. The remaining authors have no conflicts of interest.
Peer review information: Primary Handling Editor: Elena Bellafante.
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De Jesus, D.F., Zhang, Z., Kahraman, S. et al. m6A mRNA methylation regulates human β-cell biology in physiological states and in type 2 diabetes. Nat Metab 1, 765–774 (2019). https://doi.org/10.1038/s42255-019-0089-9
Genome Biology (2019)
Nature Metabolism (2019)