m 6 A mRNA Methylation Regulates Human β-Cell Biology in Physiological States and in Type 2 Diabetes
Nat Metab.. 2019-07-29;1(8):765-774.
- Abstract
- 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 involved in cell-cycle progression, insulin secretion, and the Insulin/IGF1-AKT-PDX1 pathway. Depletion of m6A levels in EndoC-βH1 induces cell-cycle arrest and impairs insulin secretion by decreasing AKT phosphorylation and PDX1 protein levels. β-cell specific Mettl14 knock-out mice, which display reduced m6A levels, mimic the islet phenotype in human T2D with early diabetes onset and mortality due 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.
- Consortium data used in this publication
- 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 microarrays data performed in mouse whole islets have been deposited under the accession code GSE132111. The data that supports the findings of this study are available from the corresponding author upon reasonable request. R package RADAR code is available upon request.