m 6 A Modification Prevents Formation of Endogenous Double-Stranded RNAs and Deleterious Innate Immune Responses during Hematopoietic Development

• Published in: Immunity (Cambridge, Mass.) Vol. 52; no. 6; p. 1007
• Main Authors: Gao, Yimeng, Vasic, Radovan, Song, Yuanbin, Teng, Rhea, Liu, Chengyang, Gbyli, Rana, Biancon, Giulia, Nelakanti, Raman, Lobben, Kirsten, Kudo, Eriko, Liu, Wei, Ardasheva, Anastasia, Fu, Xiaoying, Wang, Xiaman, Joshi, Poorval, Lee, Veronica, Dura, Burak, Viero, Gabriella, Iwasaki, Akiko, Fan, Rong, Xiao, Andrew, Flavell, Richard A, Li, Hua-Bing, Tebaldi, Toma, Halene, Stephanie
• Format: Journal Article
• Language: English
• Published: United States Elsevier Limited 16.06.2020
• Subjects: Adenosine - chemistry; Animals; Biomarkers; Bone marrow; Bone Marrow Failure Disorders - etiology; Bone Marrow Failure Disorders - metabolism; Bone Marrow Failure Disorders - pathology; Cell Differentiation - genetics; Defects; Disease Models, Animal; Double-stranded RNA; Epigenesis, Genetic; Fetuses; Gene Expression; Genes; Hematopoiesis - genetics; Hematopoiesis - immunology; Hematopoietic Stem Cells; Immune response; Immune system; Immunity, Innate - genetics; Immunophenotyping; Innate immunity; Lethality; Leukemia; Liver; Liver diseases; Mammals; Methylation; Methyltransferases - genetics; Methyltransferases - metabolism; Mice; Mice, Knockout; N6-methyladenosine; Pattern recognition; Pattern recognition receptors; Protein folding; RNA modification; RNA, Double-Stranded - chemistry; RNA, Double-Stranded - metabolism; Stem cells; dsRNA; RNA modification; hematopoietic development; N-methyladenosine; hematopoiesis; innate immune response; METTL3; m6A; epitranscriptome; double-stranded RNA
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2020.05.003

N -methyladenosine (m 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 A writer METTL3 in murine fetal liver resulted in hematopoietic failure and perinatal lethality. Loss of METTL3 and m 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 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 Mavs or Rnasel signaling partially rescued the observed hematopoietic defects in METTL3-deficient cells in vitro and in vivo. Our results suggest that m A modification protects against endogenous dsRNA formation and a deleterious innate immune response during mammalian hematopoietic development.