title: Mammalian WTAP is a regulatory subunit of the RNA N6-methyladenosine methyltransferase.
abstract: The methyltransferase like 3 (METTL3)-containing methyltransferase complex catalyzes the N6-methyladenosine (m6A) formation, a novel epitranscriptomic marker; however, the nature of this complex remains largely unknown. Here we report two new components of the human m6A methyltransferase complex, Wilms' tumor 1-associating protein (WTAP) and methyltransferase like 14 (METTL14). WTAP interacts with METTL3 and METTL14, and is required for their localization into nuclear speckles enriched with pre-mRNA processing factors and for catalytic activity of the m6A methyltransferase in vivo. The majority of RNAs bound by WTAP and METTL3 in vivo represent mRNAs containing the consensus m6A motif. In the absence of WTAP, the RNA-binding capability of METTL3 is strongly reduced, suggesting that WTAP may function to regulate recruitment of the m6A methyltransferase complex to mRNA targets. Furthermore, transcriptomic analyses in combination with photoactivatable-ribonucleoside-enhanced crosslinking and immunoprecipitation (PAR-CLIP) illustrate that WTAP and METTL3 regulate expression and alternative splicing of genes involved in transcription and RNA processing. Morpholino-mediated knockdown targeting WTAP and/or METTL3 in zebrafish embryos caused tissue differentiation defects and increased apoptosis. These findings provide strong evidence that WTAP may function as a regulatory subunit in the m6A methyltransferase complex and play a critical role in epitranscriptomic regulation of RNA metabolism.
authors.affiliation: 1] Center For Genome Variations and Precision Bio-Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China [2] University of Chinese Academy of Sciences, 19A Yuquan Road, Beijing 100049, China.
authors.forename: Xiao-Li
authors.initials: XL
authors.lastname: Ping
authors.affiliation: Center For Genome Variations and Precision Bio-Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Bao-Fa
authors.initials: BF
authors.lastname: Sun
authors.affiliation: State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Wang
authors.affiliation: 1] Center For Genome Variations and Precision Bio-Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China [2] University of Chinese Academy of Sciences, 19A Yuquan Road, Beijing 100049, China.
authors.forename: Wen
authors.initials: W
authors.lastname: Xiao
authors.affiliation: Center For Genome Variations and Precision Bio-Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Yang
authors.affiliation: Center For Genome Variations and Precision Bio-Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Wen-Jia
authors.initials: WJ
authors.lastname: Wang
authors.affiliation: Center For Genome Variations and Precision Bio-Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Samir
authors.initials: S
authors.lastname: Adhikari
authors.affiliation: Center For Genome Variations and Precision Bio-Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Center For Genome Variations and Precision Bio-Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Lv
authors.affiliation: Center For Genome Variations and Precision Bio-Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Yu-Sheng
authors.initials: YS
authors.lastname: Chen
authors.affiliation: Center For Genome Variations and Precision Bio-Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Xu
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Center For Genome Variations and Precision Bio-Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Ang
authors.initials: A
authors.lastname: Li
authors.affiliation: Center For Genome Variations and Precision Bio-Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Center For Genome Variations and Precision Bio-Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Ujwal
authors.initials: U
authors.lastname: Dahal
authors.affiliation: Chinese Academy of Sciences Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Xiao-Min
authors.initials: XM
authors.lastname: Lou
authors.affiliation: Center for Structural Biology, Ministry of Education Key Laboratory of Protein Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China.
authors.forename: Xi
authors.initials: X
authors.lastname: Liu
authors.affiliation: Life Sciences Institute, Zhejiang University, Zhejiang 310058, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Huang
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology, Tianjin 300041, China.
authors.forename: Wei-Ping
authors.initials: WP
authors.lastname: Yuan
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology, Tianjin 300041, China.
authors.forename: Xiao-Fan
authors.initials: XF
authors.lastname: Zhu
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology, Tianjin 300041, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Cheng
authors.affiliation: Center For Genome Variations and Precision Bio-Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Yong-Liang
authors.initials: YL
authors.lastname: Zhao
authors.affiliation: Center for Structural Biology, Ministry of Education Key Laboratory of Protein Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China.
authors.forename: Xinquan
authors.initials: X
authors.lastname: Wang
authors.affiliation: 1] Center For Genome Variations and Precision Bio-Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China [2] The Novo Nordisk Foundation Center for Protein Research, Ubiquitin Signalling Group, Faculty of Health Sciences, Copenhagen, Denmark.
authors.forename: Jannie M
authors.initials: JM
authors.lastname: Rendtlew Danielsen
authors.affiliation: State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Liu
authors.affiliation: 1] Center For Genome Variations and Precision Bio-Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China [2] University of Chinese Academy of Sciences, 19A Yuquan Road, Beijing 100049, China.
authors.forename: Yun-Gui
authors.initials: YG
authors.lastname: Yang
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D018797:Cell Cycle Proteins; D002454:Cell Differentiation; D002467:Cell Nucleus / Q000378:metabolism; D004625:Embryo, Nonmammalian / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008780:Methyltransferases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D034622:RNA Interference; D000072260:RNA Splicing Factors; D012333:RNA, Messenger / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D015027:Zebrafish / Q000254:growth & development
chemical_list: D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D000072260:RNA Splicing Factors; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C419554:WTAP protein, human; C587355:METTL14 protein, human; D008780:Methyltransferases; C468275:METTL3 protein, human