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

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, Yutaka Suzuki, Yukio Kawahara, Izuho Hatada, Michael C. Bassik and Osamu Takeuchi ()
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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
Michael C. Bassik: Stanford University School of Medicine
Osamu Takeuchi: Kyoto University

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-34078-y

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