SON is an essential m6A target for hematopoietic stem cell fate.

Cell stem cell 2023 Dec 07

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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. Copyright © 2023 Elsevier Inc. All rights reserved.

Citation

Hanzhi Luo, Mariela Cortés-López, Cyrus L Tam, Michael Xiao, Isaac Wakiro, Karen L Chu, Aspen Pierson, Mandy Chan, Kathryn Chang, Xuejing Yang, Daniel Fecko, Grace Han, Eun-Young Erin Ahn, Quaid D Morris, Dan A Landau, Michael G Kharas. SON is an essential m6A target for hematopoietic stem cell fate. Cell stem cell. 2023 Dec 07;30(12):1658-1673.e10