The mRNA m6A reader YTHDF2 suppresses proinflammatory pathways and sustains hematopoietic stem cell function

Christopher Mapperley, Louie N. van de Lagemaat, Hannah Lawson, Andrea Tavosanis, Jasmin Paris, Joana Campos, David Wotherspoon, Jozef Durko, Annika Sarapuu, Junho Choe, Ivayla Ivanova, Daniela S. Krause, Alex von Kriegsheim, Christian Much, Marcos Morgan, Richard I. Gregory, Adam J. Mead, Dónal O’Carroll, Kamil R. Kranc

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The mRNA N6 -methyladenosine (m6 A) modification has emerged as an essential regulator of normal and malignant hematopoiesis. Inactivation of the m6A mRNA reader YTHDF2, which recognizes m6A-modified transcripts to promote m6A-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 m6A-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 m6A in long-term HSC maintenance.
Original languageUndefined/Unknown
JournalJournal of Experimental Medicine
Early online date6 Nov 2020
Publication statusPublished - 1 Mar 2021

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