Base-Resolution Mapping Reveals Distinct m1A Methylome in Nuclear- and Mitochondrial-Encoded Transcripts

Mol Cell. 2017 Dec 7;68(5):993-1005.e9. doi: 10.1016/j.molcel.2017.10.019.

Xiaoyu Li ¹, Xushen Xiong ², Meiling Zhang ¹, Kun Wang ¹, Ying Chen ³, Jun Zhou ⁴, Yuanhui Mao ⁴, Jia Lv ⁵, Danyang Yi ¹, Xiao-Wei Chen ⁶, Chu Wang ⁷, Shu-Bing Qian ⁴, Chengqi Yi ⁸

Affiliations

1 State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing 100871, China.
2 State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing 100871, China; Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China; Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China.
3 Department of Chemical Biology and Synthetic and Functional Biomolecules Center, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China.
4 Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853, USA.
5 Institute of Molecular Medicine, Peking University, Beijing 100871, China.
6 Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China; Institute of Molecular Medicine, Peking University, Beijing 100871, China.
7 Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China; Department of Chemical Biology and Synthetic and Functional Biomolecules Center, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China.
8 State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing 100871, China; Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China; Department of Chemical Biology and Synthetic and Functional Biomolecules Center, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China. Electronic address: chengqi.yi@pku.edu.cn.

PMID: 29107537 DOI: 10.1016/j.molcel.2017.10.019

Abstract

Gene expression can be post-transcriptionally regulated via dynamic and reversible RNA modifications. N¹-methyladenosine (m¹A) is a recently identified mRNA modification; however, little is known about its precise location and biogenesis. Here, we develop a base-resolution m¹A profiling method, based on m¹A-induced misincorporation during reverse transcription, and report distinct classes of m¹A methylome in the human transcriptome. m¹A in 5' UTR, particularly those at the mRNA cap, associate with increased translation efficiency. A different, small subset of m¹A exhibit a GUUCRA tRNA-like motif, are evenly distributed in the transcriptome, and are dependent on the methyltransferase TRMT6/61A. Additionally, we show that m¹A is prevalent in the mitochondrial-encoded transcripts. Manipulation of m¹A level via TRMT61B, a mitochondria-localizing m¹A methyltransferase, demonstrates that m¹A in mitochondrial mRNA interferes with translation. Collectively, our approaches reveal distinct classes of m¹A methylome and provide a resource for functional studies of m¹A-mediated epitranscriptomic regulation.

Keywords

N(1)-methyladenosine; RNA epigenetics; RNA modification; base-resolution; epitranscriptomics; m(1)A; mitochondria; translation regulation.

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