YTHDF3 modulates hematopoietic stem cells by recognizing RNA m6A modification on Ccnd1

Hematopoietic stem cells (HSC) give rise to the cells of the blood system over the whole lifespan. N6-methyladenosine (m6A), the most prevalent RNA modification, modulates gene expression via the processes of writing and reading. Recent studies showed that m6A writer genes (Mettl3 and Mettl14) play an essential role in HSC. However, which reader deciphers the m6A modification to modulate HSC remains unknown. In this study, we observed that dysfunction of Ythdf3 and Ccnd1 severely impaired the reconstitution capacity of HSC, which phenocopies Mettl3-deficient HSC. Dysfunction of Ythdf3 and Mettl3 results in a translational defect of Ccnd1. Ythdf3 and Mettl3 regulate HSC by transmitting m6A RNA methylation on the 5' untranslated region of Ccnd1. Enforced Ccnd1 expression completely rescued the defect of Ythdf3-/- HSC and partially rescued Mettl3-compromised HSC. Taken together, this study identified, for the first time, that Ccnd1 is the target of METTL3 and YTHDF3 to transmit the m6A RNA methylation signal and thereby regulate the reconstitution capacity of HSC.

Automated summary

This study identified the role of m6A RNA modification in regulating the reconstitution capacity of HSC. Ythdf3 and Mettl3 regulate HSC by controlling the translation process of Ccnd1.