m6A mRNA Methylation Controls Functional Maturation in Neonatal Murine β-Cells.
Yanqiu WangJiajun SunZhen LinWeizhen ZhangShu WangWei-Qing WangQidi WangYanqiu WangPublished in: Diabetes (2020)
The N 6-methyladenosine (m6A) RNA modification is essential during embryonic development of various organs. However, its role in embryonic and early postnatal islet development remains unknown. Mice in which RNA methyltransferase-like 3/14 (Mettl3/14) were deleted in Ngn3+ endocrine progenitors (Mettl3/14 nKO ) developed hyperglycemia and hypoinsulinemia at 2 weeks after birth. We found that Mettl3/14 specifically regulated both functional maturation and mass expansion of neonatal β-cells before weaning. Transcriptome and m6A methylome analyses provided m6A-dependent mechanisms in regulating cell identity, insulin secretion, and proliferation in neonatal β-cells. Importantly, we found that Mettl3/14 were dispensable for β-cell differentiation but directly regulated essential transcription factor MafA expression at least partially via modulating its mRNA stability. Failure to maintain this modification impacted the ability to fulfill β-cell functional maturity. In both diabetic db/db mice and patients with type 2 diabetes (T2D), decreased Mettl3/14 expression in β-cells was observed, suggesting its possible role in T2D. Our study unraveled the essential role of Mettl3/14 in neonatal β-cell development and functional maturation, both of which determined functional β-cell mass and glycemic control in adulthood.
Keyphrases
- induced apoptosis
- transcription factor
- single cell
- cell cycle arrest
- cell therapy
- signaling pathway
- type diabetes
- glycemic control
- gene expression
- cell death
- preterm infants
- binding protein
- genome wide
- endoplasmic reticulum stress
- rna seq
- dna methylation
- intensive care unit
- pi k akt
- preterm birth
- cell proliferation
- dna binding
- mechanical ventilation
- wild type