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CompasSeq: epitranscriptome-wide percentage assessment of metabolite-capped RNA at the transcript resolution

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  • Yuanbo Liu

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Dean Li

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Xueting Wang

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Kongyan Niu

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Jun Bai

    (The Second Affiliated Hospital of Naval Medical University)

  • Lefeng Qu

    (The Second Affiliated Hospital of Naval Medical University)

  • Nan Liu

    (Chinese Academy of Sciences
    Shanghai Key Laboratory of Aging Studies)

Abstract

Nucleotide-containing metabolites, e.g., NAD, can serve as noncanonical initiating nucleotides (NCIN) during transcription, yielding NCIN-capped RNAs (NCIN-RNAs). Current profiling strategies are limited to detecting specific metabolite caps and lack an epitranscriptome-wide approach for quantifying the ratio between NCIN- and m7G-capped forms. Here, we develop the CompasSeq analytical platform, which integrates experimental and computational frameworks, enabling comprehensive and quantitative assessment of NCIN-RNAs at the transcript resolution. CompasSeq utilizes carefully devised enzymatic reactions to selectively capture NCIN-RNAs. By introducing proper spike-ins, CompasSeq can analyze the stoichiometry of NCIN caps. We further design an orthogonal method, the quantitative exoribonuclease reduction assay, to validate newly identified NCIN-RNAs and their capping ratios. Using CompasSeq, we quantify previously unexplored NCIN capping percentages from mouse liver and illustrate their age-associated dynamics. Moreover, we uncover a dichotomy between RNA expression and NCIN capping in genes impinging on age-related pathways. Our study presents both experimental and computational solutions for in-depth analysis of NCIN-RNAs, paving the road for functional investigations into NCIN-RNAs.

Suggested Citation

  • Yuanbo Liu & Dean Li & Xueting Wang & Kongyan Niu & Jun Bai & Lefeng Qu & Nan Liu, 2025. "CompasSeq: epitranscriptome-wide percentage assessment of metabolite-capped RNA at the transcript resolution," Nature Communications, Nature, vol. 16(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-61697-y
    DOI: 10.1038/s41467-025-61697-y
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    References listed on IDEAS

    as
    1. Hana Cahová & Marie-Luise Winz & Katharina Höfer & Gabriele Nübel & Andres Jäschke, 2015. "NAD captureSeq indicates NAD as a bacterial cap for a subset of regulatory RNAs," Nature, Nature, vol. 519(7543), pages 374-377, March.
    2. Xufeng Wang & Dongli Yu & Jiancheng Yu & Hao Hu & Runlai Hang & Zachary Amador & Qi Chen & Jijie Chai & Xuemei Chen, 2024. "Toll/interleukin-1 receptor (TIR) domain-containing proteins have NAD-RNA decapping activity," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    3. Yaqing Zhang & David Kuster & Tobias Schmidt & Daniel Kirrmaier & Gabriele Nübel & David Ibberson & Vladimir Benes & Hans Hombauer & Michael Knop & Andres Jäschke, 2020. "Extensive 5′-surveillance guards against non-canonical NAD-caps of nuclear mRNAs in yeast," Nature Communications, Nature, vol. 11(1), pages 1-17, December.
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