m6A mRNA Methylation Controls Functional Maturation in Neonatal Murine ß-Cells.
Diabetes
; 69(8): 1708-1722, 2020 08.
Article
in En
| MEDLINE
| ID: mdl-32404350
ABSTRACT
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 ß-cells before weaning. Transcriptome and m6A methylome analyses provided m6A-dependent mechanisms in regulating cell identity, insulin secretion, and proliferation in neonatal ß-cells. Importantly, we found that Mettl3/14 were dispensable for ß-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 ß-cell functional maturity. In both diabetic db/db mice and patients with type 2 diabetes (T2D), decreased Mettl3/14 expression in ß-cells was observed, suggesting its possible role in T2D. Our study unraveled the essential role of Mettl3/14 in neonatal ß-cell development and functional maturation, both of which determined functional ß-cell mass and glycemic control in adulthood.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
RNA, Messenger
/
Adenosine
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Diabetes Mellitus, Type 2
/
Insulin-Secreting Cells
Limits:
Animals
/
Humans
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Male
Language:
En
Journal:
Diabetes
Year:
2020
Document type:
Article
Publication country:
EEUU
/
ESTADOS UNIDOS
/
ESTADOS UNIDOS DA AMERICA
/
EUA
/
UNITED STATES
/
UNITED STATES OF AMERICA
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US
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USA