SON is an Essential MA Target for Hematopoietic Stem Cell Fate

Stem cells regulate their self-renewal and differentiation fate outcomes through both symmetric and asymmetric divisions. mA RNA methylation controls symmetric commitment and inflammation of hematopoietic stem cells (HSCs) through unknown mechanisms. Here, we demonstrate that the nuclear speckle protein SON is an essential mA target required for murine HSC self-renewal, symmetric commitment, and inflammation control. Global profiling of mA identified that mA mRNA methylation of Son increases during HSC commitment. Upon mA depletion, Son mRNA increases, but its protein is depleted. Reintroduction of SON rescues defects in HSC symmetric commitment divisions and engraftment. Conversely, Son deletion results in a loss of HSC fitness, while overexpression of SON improves mouse and human HSC engraftment potential by increasing quiescence. Mechanistically, we found that SON rescues MYC and suppresses the METTL3-HSC inflammatory gene expression program, including CCL5, through transcriptional regulation. Thus, our findings define a mA-SON-CCL5 axis that controls inflammation and HSC fate.