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  2. Nuclear retention coupled with sequential polyadenylation dictates post-transcriptional m6A modification in the nucleus

Nuclear retention coupled with sequential polyadenylation dictates post-transcriptional m6A modification in the nucleus

  • Mol Cell. 2024 Oct 3;84(19):3758-3774.e10. doi: 10.1016/j.molcel.2024.07.017.
Peng Tang 1 Jiayi Yang 2 Zonggui Chen 3 Chen Du 4 Yang Yang 5 Haiping Zhao 6 Li Huang 2 Guangnan Li 2 Feiyan Liu 2 Bei Dong 7 Ting Shan 2 Xichen Bao 7 Yu Zhou 8
Affiliations

Affiliations

  • 1 College of Life Sciences, TaiKang Center for Life and Medical Sciences, Hubei Key Laboratory of Cell Homeostasis, RNA Institute, Wuhan University, Wuhan, China; CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.
  • 2 College of Life Sciences, TaiKang Center for Life and Medical Sciences, Hubei Key Laboratory of Cell Homeostasis, RNA Institute, Wuhan University, Wuhan, China.
  • 3 Institute of Advanced Studies, Wuhan University, Wuhan, China.
  • 4 College of Life Sciences, TaiKang Center for Life and Medical Sciences, Hubei Key Laboratory of Cell Homeostasis, RNA Institute, Wuhan University, Wuhan, China; Frontier Science Center for Immunology and Metabolism, State Key Laboratory of Virology, Wuhan University, Wuhan, China.
  • 5 College of Life Sciences, TaiKang Center for Life and Medical Sciences, Hubei Key Laboratory of Cell Homeostasis, RNA Institute, Wuhan University, Wuhan, China; Institute of Pediatric Research, Children's Hospital of Soochow University, Suzhou, China.
  • 6 Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
  • 7 CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.
  • 8 College of Life Sciences, TaiKang Center for Life and Medical Sciences, Hubei Key Laboratory of Cell Homeostasis, RNA Institute, Wuhan University, Wuhan, China; Institute of Advanced Studies, Wuhan University, Wuhan, China; Frontier Science Center for Immunology and Metabolism, State Key Laboratory of Virology, Wuhan University, Wuhan, China. Electronic address: yu.zhou@whu.edu.cn.
Abstract

N6-methyladenosine (m6A) modification is deemed to be co-transcriptionally installed on pre-mRNAs, thereby influencing various downstream RNA metabolism events. However, the causal relationship between m6A modification and RNA processing is often unclear, resulting in premature or even misleading generalizations on the function of m6A modification. Here, we develop 4sU-coupled m6A-level and isoform-characterization Sequencing (4sU-m6A-LAIC-seq) and 4sU-GLORI to quantify the m6A levels for both newly synthesized and steady-state RNAs at transcript and single-base-resolution levels, respectively, which enable dissecting the relationship between m6A modification and alternative RNA polyadenylation. Unexpectedly, our results show that many m6A addition events occur post-transcriptionally, especially on transcripts with high m6A levels. Importantly, we find higher m6A levels on shorter 3' UTR isoforms, which likely result from sequential polyadenylation of longer 3' UTR isoforms with prolonged nuclear dwelling time. Therefore, m6A modification can also take place post-transcriptionally to intimately couple with Other key RNA metabolism processes to establish and dynamically regulate epi-transcriptomics in mammalian cells.

Keywords

m(6)A modification; nuclear retention; post-transcriptional RNA processing; sequential polyadenylation.

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