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; Osamu Takeuchi

doi:10.1038/s41467-022-34078-y

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

Nat Commun. 2022 Oct 28;13(1):6435. doi: 10.1038/s41467-022-34078-y.

Authors

Masanori Yoshinaga¹, Kyuho Han², David W Morgens², Takuro Horii³, Ryosuke Kobayashi³, Tatsuaki Tsuruyama⁴, Fabian Hia⁵, Shota Yasukura⁵, Asako Kajiya⁵, Ting Cai⁵, Pedro H C Cruz⁶, Alexis Vandenbon⁷, Yutaka Suzuki⁸, Yukio Kawahara⁶, Izuho Hatada^{3

9}, Michael C Bassik², Osamu Takeuchi¹⁰

Affiliations

¹ Department of Medical Chemistry, Graduate School of Medicine, Kyoto University, Kyoto, 606-8501, Japan. [email protected].
² Department of Genetics, Stanford University School of Medicine, Stanford, CA, 94305, USA.
³ Laboratory of Genome Science, Biosignal Genome Resource Center, Institute for Molecular and Cellular Regulation, Gunma University, Gunma, 371-8512, Japan.
⁴ Department of Drug and Discovery Medicine, Graduate School of Medicine, Kyoto University, Kyoto, 606-8501, Japan.
⁵ Department of Medical Chemistry, Graduate School of Medicine, Kyoto University, Kyoto, 606-8501, Japan.
⁶ Department of RNA Biology and Neuroscience, Graduate School of Medicine, Osaka University, Osaka, 565-0871, Japan.
⁷ Laboratory of Tissue Homeostasis, Institute for Life and Medical Sciences, Kyoto University, Kyoto, 606-8507, Japan.
⁸ Laboratory of Functional Genomics, Department of Medical Genome Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Chiba, 277-8562, Japan.
⁹ Viral Vector Core, Gunma University Initiative for Advanced Research (GIAR), Gunma, 371-8512, Japan.
¹⁰ Department of Medical Chemistry, Graduate School of Medicine, Kyoto University, Kyoto, 606-8501, Japan. [email protected].

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenosine / metabolism
DNA / metabolism
Erythroblasts / metabolism
Erythropoiesis* / genetics
Methylation
Methyltransferases* / metabolism
RNA, Messenger / metabolism

Substances

Methyltransferases
Adenosine
N-methyladenosine
RNA, Messenger
DNA