m6A Modification Prevents Formation of Endogenous Double-Stranded RNAs and Deleterious Innate Immune Responses during Hematopoietic Development
- PMID: 32497523
- PMCID: PMC7408742
- DOI: 10.1016/j.immuni.2020.05.003
m6A Modification Prevents Formation of Endogenous Double-Stranded RNAs and Deleterious Innate Immune Responses during Hematopoietic Development
Abstract
N6-methyladenosine (m6A) 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 m6A writer METTL3 in murine fetal liver resulted in hematopoietic failure and perinatal lethality. Loss of METTL3 and m6A activated an aberrant innate immune response, mediated by the formation of endogenous double-stranded RNAs (dsRNAs). The aberrantly formed dsRNAs were long, highly m6A 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 Mavs or Rnasel signaling partially rescued the observed hematopoietic defects in METTL3-deficient cells in vitro and in vivo. Our results suggest that m6A modification protects against endogenous dsRNA formation and a deleterious innate immune response during mammalian hematopoietic development.
Keywords: METTL3; N(6)-methyladenosine; RNA modification; double-stranded RNA; dsRNA; epitranscriptome; hematopoiesis; hematopoietic development; innate immune response; m6A.
Copyright © 2020 Elsevier Inc. All rights reserved.
Conflict of interest statement
Declaration of Interests The authors declare no competing interests.
Figures
![Figure 1.](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/7408742/bin/nihms-1596763-f0002.gif)
![Figure 2.](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/7408742/bin/nihms-1596763-f0003.gif)
![Figure 3.](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/7408742/bin/nihms-1596763-f0004.gif)
![Figure 4.](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/7408742/bin/nihms-1596763-f0005.gif)
![Figure 5.](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/7408742/bin/nihms-1596763-f0006.gif)
![Figure 6.](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/7408742/bin/nihms-1596763-f0007.gif)
![Figure 7.](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/7408742/bin/nihms-1596763-f0008.gif)
Similar articles
-
M6 A modification: A mechanism for protecting hematopoietic development in mammals.Cell Biol Int. 2021 Jan;45(1):58-60. doi: 10.1002/cbin.11471. Epub 2020 Oct 9. Cell Biol Int. 2021. PMID: 32997376 Review.
-
N6-methyladenosine RNA modification suppresses antiviral innate sensing pathways via reshaping double-stranded RNA.Nat Commun. 2021 Mar 11;12(1):1582. doi: 10.1038/s41467-021-21904-y. Nat Commun. 2021. PMID: 33707441 Free PMC article.
-
The N6-Methyladenosine mRNA Methylase METTL3 Controls Cardiac Homeostasis and Hypertrophy.Circulation. 2019 Jan 22;139(4):533-545. doi: 10.1161/CIRCULATIONAHA.118.036146. Circulation. 2019. PMID: 30586742 Free PMC article.
-
Transcriptome-wide quantification of double-stranded RNAs in live mouse tissues by dsRIP-Seq.STAR Protoc. 2021 Mar 18;2(1):100366. doi: 10.1016/j.xpro.2021.100366. eCollection 2021 Mar 19. STAR Protoc. 2021. PMID: 33778776 Free PMC article.
-
RNA N 6-Methyladenosine Modification in Normal and Malignant Hematopoiesis.Adv Exp Med Biol. 2019;1143:75-93. doi: 10.1007/978-981-13-7342-8_4. Adv Exp Med Biol. 2019. PMID: 31338816 Review.
Cited by
-
Inverted Alu repeats: friends or foes in the human transcriptome.Exp Mol Med. 2024 Jun;56(6):1250-1262. doi: 10.1038/s12276-024-01177-3. Epub 2024 Jun 14. Exp Mol Med. 2024. PMID: 38871814 Free PMC article. Review.
-
Navigating the landscape of epitranscriptomics and host immunity.Genome Res. 2024 May 15;34(4):515-529. doi: 10.1101/gr.278412.123. Genome Res. 2024. PMID: 38702197 Review.
-
Replicative senescence and high glucose induce the accrual of self-derived cytosolic nucleic acids in human endothelial cells.Cell Death Discov. 2024 Apr 20;10(1):184. doi: 10.1038/s41420-024-01954-z. Cell Death Discov. 2024. PMID: 38643201 Free PMC article.
-
A Mettl16/m6A/mybl2b/Igf2bp1 axis ensures cell cycle progression of embryonic hematopoietic stem and progenitor cells.EMBO J. 2024 May;43(10):1990-2014. doi: 10.1038/s44318-024-00082-9. Epub 2024 Apr 11. EMBO J. 2024. PMID: 38605226 Free PMC article.
-
Interpreting single-cell messages in normal and aberrant hematopoiesis with the Cell Marker Accordion.bioRxiv [Preprint]. 2024 Mar 12:2024.03.08.584053. doi: 10.1101/2024.03.08.584053. bioRxiv. 2024. PMID: 38559181 Free PMC article. Preprint.
References
Publication types
MeSH terms
Substances
Grants and funding
LinkOut - more resources
Full Text Sources
Other Literature Sources
Molecular Biology Databases
Miscellaneous