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The N6-methyladenosine methyltransferase METTL16 enables erythropoiesis through safeguarding genome integrity

Author

Listed:
  • Masanori Yoshinaga

    (Kyoto University)

  • Kyuho Han

    (Stanford University School of Medicine)

  • David W. Morgens

    (Stanford University School of Medicine)

  • Takuro Horii

    (Gunma University)

  • Ryosuke Kobayashi

    (Gunma University)

  • Tatsuaki Tsuruyama

    (Kyoto University)

  • Fabian Hia

    (Kyoto University)

  • Shota Yasukura

    (Kyoto University)

  • Asako Kajiya

    (Kyoto University)

  • Ting Cai

    (Kyoto University)

  • Pedro H. C. Cruz

    (Osaka University)

  • Alexis Vandenbon

    (Kyoto University)

  • Yutaka Suzuki

    (The University of Tokyo)

  • Yukio Kawahara

    (Osaka University)

  • Izuho Hatada

    (Gunma University
    Gunma University Initiative for Advanced Research (GIAR))

  • Michael C. Bassik

    (Stanford University School of Medicine)

  • Osamu Takeuchi

    (Kyoto University)

Abstract

During erythroid differentiation, the maintenance of genome integrity is key for the success of multiple rounds of cell division. However, molecular mechanisms coordinating the expression of DNA repair machinery in erythroid progenitors are poorly understood. Here, we discover that an RNA N6-methyladenosine (m6A) methyltransferase, METTL16, plays an essential role in proper erythropoiesis by safeguarding genome integrity via the control of DNA-repair-related genes. METTL16-deficient erythroblasts exhibit defective differentiation capacity, DNA damage and activation of the apoptotic program. Mechanistically, METTL16 controls m6A deposition at the structured motifs in DNA-repair-related transcripts including Brca2 and Fancm mRNAs, thereby upregulating their expression. Furthermore, a pairwise CRISPRi screen revealed that the MTR4-nuclear RNA exosome complex is involved in the regulation of METTL16 substrate mRNAs in erythroblasts. Collectively, our study uncovers that METTL16 and the MTR4-nuclear RNA exosome act as essential regulatory machinery to maintain genome integrity and erythropoiesis.

Suggested Citation

  • Masanori Yoshinaga & Kyuho Han & David W. Morgens & Takuro Horii & Ryosuke Kobayashi & Tatsuaki Tsuruyama & Fabian Hia & Shota Yasukura & Asako Kajiya & Ting Cai & Pedro H. C. Cruz & Alexis Vandenbon , 2022. "The N6-methyladenosine methyltransferase METTL16 enables erythropoiesis through safeguarding genome integrity," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-34078-y
    DOI: 10.1038/s41467-022-34078-y
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