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<p>The extent to which an RNA folds into structure ensembles and how different structures in the ensemble regulate eukaryotic gene expression is not fully understood. Here, we coupled chemical probing with direct RNA sequencing to identify structure modifications along a single RNA molecule (sm-PORE-cupine). We used direct signal alignment in addition to base mapping to increase the percentage of mappable sequences and showed that Bernoulli mixture model clustering can separate structure ensembles accurately. We applied sm-PORE-cupine to identify isoform-specific structure ensembles along the SARS-CoV-2 genome and structure ensembles in the <i>Candida albicans</i> transcriptome. We observed that RNAs are more structurally homogeneous in vitro, at higher temperatures and in the 3′ untranslated regions of <i>C. albicans</i>. Structure ensembles are associated with changes in translation efficiency and decay in <i>C. albicans</i>, and we validated translation changes using reporter assays. sm-PORE-cupine expands the existing toolbox for studying RNA structure and function in diverse transcriptomes.</p>

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Direct RNA sequencing and signal alignment reveal RNA structure ensembles in a eukaryotic cell

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月24日

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  • Jiaxu Wang,
  • Jian Han,
  • Wen Ting Tan,
  • Anthony Youzhi Cheng,
  • Jong Ghut Ashley Aw,
  • Yue Wang,
  • Guisheng Zeng,
  • Niranjan Nagarajan,
  • Yue Wan

摘要

The extent to which an RNA folds into structure ensembles and how different structures in the ensemble regulate eukaryotic gene expression is not fully understood. Here, we coupled chemical probing with direct RNA sequencing to identify structure modifications along a single RNA molecule (sm-PORE-cupine). We used direct signal alignment in addition to base mapping to increase the percentage of mappable sequences and showed that Bernoulli mixture model clustering can separate structure ensembles accurately. We applied sm-PORE-cupine to identify isoform-specific structure ensembles along the SARS-CoV-2 genome and structure ensembles in the Candida albicans transcriptome. We observed that RNAs are more structurally homogeneous in vitro, at higher temperatures and in the 3′ untranslated regions of C. albicans. Structure ensembles are associated with changes in translation efficiency and decay in C. albicans, and we validated translation changes using reporter assays. sm-PORE-cupine expands the existing toolbox for studying RNA structure and function in diverse transcriptomes.