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

• DOI: 10.1038/s41467-022-34078-y
• Publication Date: 2022-10-28T12:15:56Z
• Authors: 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
• Keywords: Safeguarding; N6-Methyladenosine; Epigenome

Abstract During erythroid differentiation, the maintenance of genome integrity is key for success multiple rounds cell division. However, molecular mechanisms coordinating expression DNA repair machinery in progenitors are poorly understood. Here, we discover that an RNA N 6 -methyladenosine (m A) methyltransferase, METTL16, plays essential role proper erythropoiesis by safeguarding via control DNA-repair-related genes. METTL16-deficient erythroblasts exhibit defective differentiation capacity, damage and activation apoptotic program. Mechanistically, METTL16 controls m A deposition at structured motifs transcripts including Brca2 Fancm mRNAs, thereby upregulating their expression. Furthermore, a pairwise CRISPRi screen revealed MTR4-nuclear exosome complex involved regulation substrate mRNAs erythroblasts. Collectively, our study uncovers act as regulatory to maintain erythropoiesis.