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      m(6)A RNA methylation is regulated by microRNAs and promotes reprogramming to pluripotency.

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          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.

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          Author and article information

          Journal
          Cell Stem Cell
          Cell stem cell
          1875-9777
          1875-9777
          Mar 5 2015
          : 16
          : 3
          Affiliations
          [1 ] 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.
          [2 ] 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.
          [3 ] State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
          [4 ] 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.
          [5 ] 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.
          [6 ] 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.
          [7 ] State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China.
          [8 ] State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
          [9 ] 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.
          [10 ] 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.
          [11 ] State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China. Electronic address: qzhou@ioz.ac.cn.
          Article
          S1934-5909(15)00017-X
          10.1016/j.stem.2015.01.016
          25683224
          612de731-c5fb-4d6e-95dd-be4d82511fd5
          Copyright © 2015 Elsevier Inc. All rights reserved.

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