Mettl3–Mettl14 methyltransferase complex regulates the quiescence of adult hematopoietic stem cells

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N⁶-methyladenosine (m⁶A) is a common modification of mRNA that is catalyzed by the Mettl3–Mettl14 methyltransferase complex¹, with WTAP as its regulatory subunit². The physiological importance of m⁶A has been evidenced by its pivotal roles in tissue development and differentiation^{3,4,5,6,7,8,9}. Hematopoietic stem cells (HSCs) are self-renewable multipotent progenitor cells that sustain all blood cell lineages throughout life. It has been well recognized that epigenetic modifications, such as histone or DNA modifications, are implicated in HSC self-renewal¹⁰. Recent studies have shown that the mRNA modification m⁶A also functions in the hematopoietic system. In human, Mettl3–Mettl14-mediated m⁶A was found to promote the development of acute myeloid leukemia and maintain leukemia-initiating cells^5,6,11. In zebrafish and mouse, knockdown of Mettl3 blocked the endothelial-to-hematopoietic transition during embryonic development, thereby repressing the generation of the earliest HSCs⁷. Surprisingly, deletion of Mettl3 in Vav1-cre; Mettl3^fl/fl mouse embryos did not have a significant effect on the number or function of E10.5 fetal hematopoietic stem and progenitor cells (HSPCs)⁴, suggesting that cell-autonomous m⁶A is dispensable for HSC self-renewal during early development. Conditional deletion of Mettl14 in adult mice caused a mild but significant reduction of the hematopoietic repopulation ability in recipient mice⁶. The repopulation defect observed in Mettl14-deficient bone marrow cells could be interpreted as a myeloid differentiation defect or a defect in HSC self-renewal. However, until now, there is a lack of evidence that m⁶A plays a role in HSC self-renewal in the bone marrow. In this study, we took genetic approaches to investigate the physiological roles of Mettl3 and Mettl14 in the regulation of HSC self-renewal in adult mouse bone marrow.

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