RNA m5C methylation mediated by Ybx1 ensures hematopoietic stem and progenitor cell expansion

Hematopoietic stem and progenitor cells (HSPCs) undergo rapid transcriptional transitions among distinct cell states and functional properties during development, but the underlying molecular mechanism is largely unknown. Here, we characterize the mRNA m5C landscape of developing HSPCs in zebrafish and found that m5C modification is essential for HSPC expansion through maintaining mRNA stability. Deletion of the m5C reader, Y-box binding protein 1 (Ybx1), significantly inhibits the proliferation of HSPCs in zebrafish and mice. Mechanistically, Ybx1 recognizes m5C-modified mRNAs and maintains the stability of cell-cycle-related transcripts, thereby ensuring proper HSPC expansion. This study reveals the critical role of Ybx1-mediated mRNA m5C modification in developmental hematopoiesis and provides new insights and epitransciptomic strategies for optimizing HSPC expansion.