Loss of YTHDF2-mediated m⁶A-dependent mRNA clearance facilitates hematopoietic stem cell regeneration

Dear Editor,

Hematopoietic stem cells (HSCs) have unique self-renewal capacity to replenish the entire blood system, which is essential for various stress conditions, such as serial transplantation, ionizing radiation, anti-cancer medication, hemorrhage or infection.¹ N⁶-methyl-adenosine (m⁶A), the most prevalent reversible nucleotide modification in cellular mRNA in eukaryotes,² is associated with the maturation, translation, and eventual decay of protein-coding transcripts.^3,4 “Reader” proteins of m⁶A modification mediate many of the properties of m⁶A-methylated transcripts through methyl-specific RNA binding.^5,6 Although the function of m⁶A modification in cell fate decision of embryonic stem cells and hematopoietic stem and progenitor cells (HSPCs) has been recently reported,^7,8 the role of “Reader” proteins in HSC function has not been reported yet, especially under hematological stresses. It is of great importance to understand how HSCs recognize and respond to such modifications. Here, we investigated the “Reader” protein of m⁶A modification in HSC homeostasis and regeneration upon various stresses.

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