title: m(6)A RNA methylation is regulated by microRNAs and promotes reprogramming to pluripotency.
abstract: N(6)-methyladenosine (m(6)A) has been recently identified as a conserved epitranscriptomic modification of eukaryotic mRNAs, but its features, regulatory mechanisms, and functions in cell reprogramming are largely unknown. Here, we report m(6)A modification profiles in the mRNA transcriptomes of four cell types with different degrees of pluripotency. Comparative analysis reveals several features of m(6)A, especially gene- and cell-type-specific m(6)A mRNA modifications. We also show that microRNAs (miRNAs) regulate m(6)A modification via a sequence pairing mechanism. Manipulation of miRNA expression or sequences alters m(6)A modification levels through modulating the binding of METTL3 methyltransferase to mRNAs containing miRNA targeting sites. Increased m(6)A abundance promotes the reprogramming of mouse embryonic fibroblasts (MEFs) to pluripotent stem cells; conversely, reduced m(6)A levels impede reprogramming. Our results therefore uncover a role for miRNAs in regulating m(6)A formation of mRNAs and provide a foundation for future functional studies of m(6)A modification in cell reprogramming.
authors: Key Laboratory of Genetic Network Biology, Collaborative Innovation Center of Genetics and Development, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China.
authors: Tong
authors: T
authors: Chen
authors: Key Laboratory of Genomics and Precision Medicine, Collaborative Innovation Center of Genetics and Development, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China.
authors: Ya-Juan
authors: YJ
authors: Hao
authors: State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
authors: Ying
authors: Y
authors: Zhang
authors: Key Laboratory of Genomics and Precision Medicine, Collaborative Innovation Center of Genetics and Development, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China.
authors: Miao-Miao
authors: MM
authors: Li
authors: Key Laboratory of Genetic Network Biology, Collaborative Innovation Center of Genetics and Development, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China.
authors: Meng
authors: M
authors: Wang
authors: State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China.
authors: Weifang
authors: W
authors: Han
authors: Key Laboratory of Genomics and Precision Medicine, Collaborative Innovation Center of Genetics and Development, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China.
authors: Yongsheng
authors: Y
authors: Wu
authors: Key Laboratory of Genomics and Precision Medicine, Collaborative Innovation Center of Genetics and Development, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China.
authors: Ying
authors: Y
authors: Lv
authors: State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
authors: Jie
authors: J
authors: Hao
authors: State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China.
authors: Libin
authors: L
authors: Wang
authors: Key Laboratory of Genomics and Precision Medicine, Collaborative Innovation Center of Genetics and Development, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China.
authors: Ang
authors: A
authors: Li
authors: Key Laboratory of Genomics and Precision Medicine, Collaborative Innovation Center of Genetics and Development, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China.
authors: Ying
authors: Y
authors: Yang
authors: Key Laboratory of Genomics and Precision Medicine, Collaborative Innovation Center of Genetics and Development, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China.
authors: Kang-Xuan
authors: KX
authors: Jin
authors: Key Laboratory of Genomics and Precision Medicine, Collaborative Innovation Center of Genetics and Development, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China.
authors: Xu
authors: X
authors: Zhao
authors: State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
authors: Yuhuan
authors: Y
authors: Li
authors: Key Laboratory of Genomics and Precision Medicine, Collaborative Innovation Center of Genetics and Development, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China.
authors: Xiao-Li
authors: XL
authors: Ping
authors: State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China.
authors: Wei-Yi
authors: WY
authors: Lai
authors: State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors: Li-Gang
authors: LG
authors: Wu
authors: State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China.
authors: Guibin
authors: G
authors: Jiang
authors: State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China.
authors: Hai-Lin
authors: HL
authors: Wang
authors: State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China.
authors: Lisi
authors: L
authors: Sang
authors: Key Laboratory of Genetic Network Biology, Collaborative Innovation Center of Genetics and Development, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China. Electronic address: xjwang@genetics.ac.cn.
authors: Xiu-Jie
authors: XJ
authors: Wang
authors: Key Laboratory of Genomics and Precision Medicine, Collaborative Innovation Center of Genetics and Development, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China. Electronic address: ygyang@big.ac.cn.
authors: Yun-Gui
authors: YG
authors: Yang
authors: State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China. Electronic address: qzhou@ioz.ac.cn.
authors: Qi
authors: Q
authors: Zhou
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000378:metabolism; D000818:Animals; D065150:Cellular Reprogramming / Q000502:physiology*; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D008745:Methylation; D008780:Methyltransferases / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D039904:Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism*; D012323:RNA Processing, Post-Transcriptional / Q000502:physiology*
chemical_list: D000225:Adenine; D008780:Methyltransferases; C000596366:Mettl3 protein, mouse; C000730567:6-methyladenine