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
Hanzhi Luo
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; Molecular Biology and Biochemistry, Simon Fraser University, Vancouver, BC, Canada
Franco Izzo
New York Genome Center, New York, NY, USA; Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA; Molecular Biology and Biochemistry, Simon Fraser University, Vancouver, BC, Canada
Brian F. Pickering
Department of Pharmacology, Weill Cornell Medicine, Cornell University, New York, NY, USA
Diu Nguyen
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
Robert Myers
New York Genome Center, New York, NY, USA; Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA
Alexandra Schurer
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
Saroj Gourkanti
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
Jens C. Brüning
Department of Mouse Genetics and Metabolism, Institute for Genetics and Center for Molecular Medicine (CMMC), University of Cologne, Zülpicher Strasse 47b, 50674 Cologne, Germany
Ly P. Vu
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
Samie R. Jaffrey
Department of Pharmacology, Weill Cornell Medicine, Cornell University, New York, NY, USA
Dan A. Landau
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; Corresponding author
Michael G. Kharas
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; Corresponding author
Summary: 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. Keywords: m6A, RNA methylation, hematopoietic stem cell, cell identity, symmetric and asymmetric cell division, MYC
