期刊
IMMUNITY
卷 52, 期 6, 页码 1007-+出版社
CELL PRESS
DOI: 10.1016/j.immuni.2020.05.003
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资金
- State of Connecticut under the Regenerative Medicine Research Fund
- NIH/NIDDK [R01DK102792]
- Frederick A. Deluca Foundation
- National Natural Science Foundation of China [81801588, 91753141]
- Program for Professor of Special Appointment (Eastern Scholar) at Shanghai Institutions of Higher Learning
- Howard Hughes Medical Institute
- James Hudson Brown-Alexander Brown Coxe Postdoctoral Fellowships
- American Society of Hematology Physician Scientist Career Development Award
- William U. Gardner Memorial Student Research Fellowship
- Yale Cooperative Center of Excellence in Hematology (YCCEH) (NIDDK) [U54DK106857]
- CNR Short Term Mobility 2018
- Young Scientists Fund of the National Natural Science Foundation of China [81800122]
- Animal Modeling Core of the Yale Cooperative Center of Excellence in Hematology (NIDDK) [U54DK106857]
N-6-methyladenosine (m(6)A) is the most abundant RNA modification, but little is known about its role in mammalian hematopoietic development. Here, we show that conditional deletion of the m(6)A writer METTL3 in murine fetal liver resulted in hematopoietic failure and perinatal lethality. Loss of METTL3 and m(6)A activated an aberrant innate immune response, mediated by the formation of endogenous double-stranded RNAs (dsRNAs). The aberrantly formed dsRNAs were long, highly m(6)A modified in their native state, characterized by low folding energies, and predominantly protein coding. We identified coinciding activation of pattern recognition receptor pathways normally tasked with the detection of foreign dsRNAs. Disruption of the aberrant immune response via abrogation of downstream Mays or Rnasel signaling partially rescued the observed hematopoietic defects in METTL3-deficient cells in vitro and in vivo. Our results suggest that m(6)A modification protects against endogenous dsRNA formation and a deleterious innate immune response during mammalian hematopoietic development.
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