Volume 24, No 2, Feb 2014
ISSN: 1001-0602
EISSN: 1748-7838 2018
impact factor 17.848*
(Clarivate Analytics, 2019)
Volume 24 Issue 2, February 2014: 177-189 | Open Access
ORIGINAL ARTICLES
Mammalian WTAP is a regulatory subunit of the RNA N6-methyladenosine methyltransferase
Xiao-Li Ping1,8,*, Bao-Fa Sun1,*, Lu Wang2,*, Wen Xiao1,8,*, Xin Yang1, Wen-Jia Wang1, Samir Adhikari1, Yue Shi1, Ying Lv1, Yu-Sheng Chen1, Xu Zhao1, Ang Li1, Ying Yang1, Ujwal Dahal1, Xiao-Min Lou3, Xi Liu4, Jun Huang5, Wei-Ping Yuan6, Xiao-Fan Zhu6, Tao Cheng6, Yong-Liang Zhao1, Xinquan Wang4, Jannie M Rendtlew Danielsen1,7, Feng Liu2 and Yun-Gui Yang1,8
1Center For Genome Variations and Precision Bio-Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China
2State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
3Chinese Academy of Sciences Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China
4Center for Structural Biology, Ministry of Education Key Laboratory of Protein Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China
5Life Sciences Institute, Zhejiang University, Zhejiang 310058, China
6State Key Laboratory of Experimental Hematology, Institute of Hematology, Tianjin 300041, China
7The Novo Nordisk Foundation Center for Protein Research, Ubiquitin Signalling Group, Faculty of Health Sciences, Copenhagen, Denmark
8University of Chinese Academy of Sciences, 19A Yuquan Road, Beijing 100049, China
Correspondence: Yun-Gui Yang, E-mail: ygyang@big.ac.cn; Feng Liu,(liuf@ioz.ac.cn)
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.
10.1038/cr.2014.3
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