m6A RNA Methylation Maintains Hematopoietic Stem Cell Identity and Symmetric Commitment

Yuanming Cheng, Hanzhi Luo, Franco Izzo, Brian F. Pickering, Diu Nguyen, Robert Myers, Alexandra Schurer, Saroj Gourkanti, Jens C. Bruening, Ly P. Vu, Samie R. Jaffrey, Dan A. Landau, Michael G. Kharas

Research output: Contribution to journalArticlepeer-review

120 Scopus citations

Abstract

Stem cells balance cellular fates through asymmetric and symmetric divisions in order to self-renew or to generate downstream progenitors. Symmetric commitment divisions in stem cells are required for rapid regeneration during tissue damage and stress. The control of symmetric commitment remains poorly defined. Using single-cell RNA sequencing (scRNA-seq) in combination with transcriptomic profiling of HSPCs (hematopoietic stem and progenitor cells) from control and m6A methyltransferase Mettl3 conditional knockout mice, we found that m6A-deficient hematopoietic stem cells (HSCs) fail to symmetrically differentiate. Dividing HSCs are expanded and are blocked in an intermediate state that molecularly and functionally resembles multipotent progenitors. Mechanistically, RNA methylation controls Myc mRNA abundance in differentiating HSCs. We identified MYC as a marker for HSC asymmetric and symmetric commitment. Overall, our results indicate that RNA methylation controls symmetric commitment and cell identity of HSCs and may provide a general mechanism for how stem cells regulate differentiation fate choice. Cheng et al. uncover RNA methylation as a guardian in hematopoietic stem cell (HSC) fate decisions. m6A maintains hematopoietic stem cell symmetric commitment and identity. This study may provide a general mechanism for how RNA methylation controls cellular fate.

Original languageEnglish
Pages (from-to) 1703-1716
Number of pages20
JournalCell Reports
Volume28
Issue number7
DOIs
StatePublished - Aug 13 2019
Externally publishedYes

Keywords

  • MYC
  • RNA methylation
  • cell identity
  • hematopoietic stem cell
  • mA
  • symmetric and asymmetric cell division

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