SON is an essential m⁶A target for hematopoietic stem cell fate

Stem cells regulate their self-renewal and differentiation fate outcomes through both symmetric and asymmetric divisions. m⁶A 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 m⁶A target required for murine HSC self-renewal, symmetric commitment, and inflammation control. Global profiling of m⁶A identified that m⁶A mRNA methylation of Son increases during HSC commitment. Upon m⁶A 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 m⁶A-SON-CCL5 axis that controls inflammation and HSC fate.