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Cell Rep. 2019 Aug 13;28(7):1703-1716.e6. doi: 10.1016/j.celrep.2019.07.032.

m6A RNA Methylation Maintains Hematopoietic Stem Cell Identity and Symmetric Commitment.

Author information

1
Molecular Pharmacology Program, Center for Cell Engineering, Center for Stem Cell Biology, Center for Experimental Therapeutics, Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
2
New York Genome Center, New York, NY, USA; Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA.
3
Department of Pharmacology, Weill Cornell Medicine, Cornell University, New York, NY, USA.
4
Department of Mouse Genetics and Metabolism, Institute for Genetics and Center for Molecular Medicine (CMMC), University of Cologne, Zülpicher Strasse 47b, 50674 Cologne, Germany.
5
Molecular Pharmacology Program, Center for Cell Engineering, Center for Stem Cell Biology, Center for Experimental Therapeutics, Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Terry Fox Laboratory, British Columbia Cancer Research Centre, Vancouver, BC, Canada; Molecular Biology and Biochemistry, Simon Fraser University, Vancouver, BC, Canada.
6
New York Genome Center, New York, NY, USA; Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA; Institute of Computational Biomedicine, Weill Cornell Medicine, New York, NY, USA. Electronic address: dal3005@med.cornell.edu.
7
Molecular Pharmacology Program, Center for Cell Engineering, Center for Stem Cell Biology, Center for Experimental Therapeutics, Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Electronic address: kharasm@mskcc.org.

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.

KEYWORDS:

MYC; RNA methylation; cell identity; hematopoietic stem cell; m(6)A; symmetric and asymmetric cell division

PMID:
31412241
DOI:
10.1016/j.celrep.2019.07.032
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