SON is an essential m(6)A target for hematopoietic stem cell fate Journal Article
| Authors: | Luo, H.; Cortés-López, M.; Tam, C. L.; Xiao, M.; Wakiro, I.; Chu, K. L.; Pierson, A.; Chan, M.; Chang, K.; Yang, X.; Fecko, D.; Han, G.; Ahn, E. Y. E.; Morris, Q. D.; Landau, D. A.; Kharas, M. G. |
| Article Title: | SON is an essential m(6)A target for hematopoietic stem cell fate |
| Abstract: | 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. © 2023 Elsevier Inc. |
| Keywords: | methylation; genetics; mouse; animal; metabolism; animals; mice; inflammation; cell fate; cell differentiation; methyltransferase; methyltransferases; messenger rna; rna, messenger; hematopoietic stem cells; stem cells; hematopoietic stem cell; differentiation; rna methylation; humans; human; rna binding proteins; rna modifications; nuclear speckles; son; mettl3 protein, human |
| Journal Title: | Cell Stem Cell |
| Volume: | 30 |
| Issue: | 12 |
| ISSN: | 1934-5909 |
| Publisher: | Cell Press |
| Date Published: | 2023-12-07 |
| Start Page: | 1658 |
| End Page: | 1673.e10 |
| Language: | English |
| DOI: | 10.1016/j.stem.2023.11.006 |
| PUBMED: | 38065069 |
| PROVIDER: | scopus |
| PMCID: | PMC10752439 |
| DOI/URL: | |
| Notes: | Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PDF and PubMed -- MSK corresponding author is Michael Kharas -- MSK author Long Yat Tam's listed with the first name 'Cyrus' on the original publication -- Source: Scopus |
