The mRNA m(6)A reader YTHDF2 suppresses proinflammatory pathways and sustains hematopoietic stem cell functionopen access
- Authors
- Mapperley, Christopher; van de Lagemaat, Louie N.; Lawson, Hannah; Tavosanis, Andrea; Paris, Jasmin; Campos, Joana; Wotherspoon, David; Durko, Jozef; Sarapuu, Annika; Choe, Junho; Ivanova, Ivayla; Krause, Daniela S.; von Kriegsheim, Alex; Much, Christian; Morgan, Marcos; Gregory, Richard I.; Mead, Adam J.; O'Carroll, Donal; Kranc, Kamil R.
- Issue Date
- Mar-2021
- Publisher
- ROCKEFELLER UNIV PRESS
- Citation
- JOURNAL OF EXPERIMENTAL MEDICINE, v.218, no.3, pp.1 - 11
- Indexed
- SCIE
SCOPUS
- Journal Title
- JOURNAL OF EXPERIMENTAL MEDICINE
- Volume
- 218
- Number
- 3
- Start Page
- 1
- End Page
- 11
- URI
- https://scholarworks.bwise.kr/hanyang/handle/2021.sw.hanyang/1317
- DOI
- 10.1084/jem.20200829
- ISSN
- 0022-1007
- Abstract
- The mRNA N-6-methyladenosine (m(6)A) modification has emerged as an essential regulator of normal and malignant hematopoiesis. Inactivation of the m(6)A mRNA reader YTHDF2, which recognizes m(6)A-modified transcripts to promote m(6)A-mRNA degradation, results in hematopoietic stem cell (HSC) expansion and compromises acute myeloid leukemia. Here we investigate the long-term impact of YTHDF2 deletion on HSC maintenance and multilineage hematopoiesis. We demonstrate that Ythdf2-deficient HSCs from young mice fail upon serial transplantation, display increased abundance of multiple m(6)A-modified inflammation-related transcripts, and chronically activate proinflammatory pathways. Consistent with the detrimental consequences of chronic activation of inflammatory pathways in HSCs, hematopoiesis-specific Ythdf2 deficiency results in a progressive myeloid bias, loss of lymphoid potential, HSC expansion, and failure of aged Ythdf2-deficient HSCs to reconstitute multilineage hematopoiesis. Experimentally induced inflammation increases YTHDF2 expression, and YTHDF2 is required to protect HSCs from this insult. Thus, our study positions YTHDF2 as a repressor of inflammatory pathways in HSCs and highlights the significance of m(6)A in long-term HSC maintenance.
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