Loss of Myc mRNA Methylation Breaks the Symmetry of Hematopoietic Stem Cells

Review of “m6A RNA Methylation Maintains Hematopoietic Stem Cell Identity and Symmetric Commitment” from Cell Reports by Stuart P. Atkinson

The METTL3-mediated N6-methyladenosine (m6A) modification of mRNA controls cell states in a context-dependent manner, and several recent studies have discovered that m6A and METTL3 contribute to the survival and maintenance of myeloid leukemia cells [1-3]. This finding has prompted the development of METTL3-targeted therapeutics; however, the disruption of m6A regulators can also significantly impact normal hematopoietic stem cell (HSC) function [4-6].

Researcher from the laboratories of Dan A. Landau (Weill Cornell Medicine) and Michael G. Kharas (Memorial Sloan Kettering Cancer Center, New York, NY, USA) sought to understand the influence of m6A-modified mRNA on HSCs with a focus on MYC given reports stating MYC as a major target of m6A that contributes to the effects of m6A in myeloid leukemia and in HSCs [2, 4]. In their new study published in Cell Reports, Cheng et al. now report that the m6A modification helps to regulate symmetric commitment of HSCs by controlling Myc mRNA stability [7].

Initial analyses combining single-cell RNA sequencing with transcriptomic profiling of hematopoietic stem and progenitor cells (HSPCs) from control and Mettl3 conditional knockout (cKO) mice revealed that Mettl3-cKO HSCs failed to symmetrically differentiate, a mechanism required for the amplification of HSCs for rapid regeneration during tissue damage and stress. The failure prompted the depletion of HSCs and the expansion of a population of cells trapped in an intermediate state, with resultant cells resembling normal multipotent progenitors at the molecular and functional levels in that they become exhausted and display reduced self-renewal in vivo.

Mechanistically, the authors discovered that symmetric division step in hematopoietic differentiation required m6A methylation and, specifically, the modification and increased stability of Myc. MYC mRNA and protein can be segregated either asymmetrically or symmetrically during HSC division, with the loss of m6A methylation reducing Myc RNA stability, thereby promoting the establishment of the metabolically active “asymmetric” HSC-like intermediate population.

Overall, this fascinating new study of the hematopoietic system highlights the essential role of RNA methylation in adult stem cell commitment and fate determination. For more on stem cell commitment and the role of mRNA modification, stay tuned to the Stem Cells Portal!

References

1. Barbieri I, Tzelepis K, Pandolfini L, et al., Promoter-bound METTL3 maintains myeloid leukaemia by m6A-dependent translation control. Nature 2017;552:126.
2. Vu LP, Pickering BF, Cheng Y, et al., The N6-methyladenosine (m6A)-forming enzyme METTL3 controls myeloid differentiation of normal hematopoietic and leukemia cells. Nature Medicine 2017;23:1369.
3. Weng H, Huang H, Wu H, et al., METTL14 Inhibits Hematopoietic Stem/Progenitor Differentiation and Promotes Leukemogenesis via mRNA m6A Modification. Cell Stem Cell 2018;22:191-205.e9.
4. Lee H, Bao S, Qian Y, et al., Stage-specific requirement for Mettl3-dependent m6A mRNA methylation during haematopoietic stem cell differentiation. Nature Cell Biology 2019;21:700-709.
5. Li Z, Qian P, Shao W, et al., Suppression of m6A reader Ythdf2 promotes hematopoietic stem cell expansion. Cell Research 2018;28:904-917.
6. Yao QJ, Sang L, Lin M, et al., Mettl3–Mettl14 methyltransferase complex regulates the quiescence of adult hematopoietic stem cells. Cell Research 2018;28:952-954.
7. Cheng Y, Luo H, Izzo F, et al., m6A RNA Methylation Maintains Hematopoietic Stem Cell Identity and Symmetric Commitment. Cell Reports 2019;28:1703-1716.e6.