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<p>Alternative splicing is a key mechanism for expanding transcriptomic and proteomic complexity, yet its role in innate immune activation remains incompletely understood. Here, we applied Oxford Nanopore native RNA-sequencing to generate an isoform-level transcriptome of primary human monocytes before and after activation with lipopolysaccharide. We identify over 24,000 expressed isoforms, including thousands of previously unannotated variants. Activation induced widespread isoform-specific expression changes, leading to extensive isoform switching events, which were validated using matched short-read RNA-Seq. These activation-induced shifts enhanced transcript immune-regulatory functions: activated monocytes preferentially express longer, coding-competent isoforms with complete open reading frames, fewer retained introns, and increased domain complexity. By integrating matched Ribo-seq and proteomic data, we demonstrate that these isoform modulations are associated with enhanced translation of immune effector proteins. Together, our findings position alternative splicing as a dynamic and functional regulator of monocyte activation, emphasizing the need for isoform-level resolution to fully understand immune cell function.</p>

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Native long-read RNA sequencing of human monocytes reveals activation-induced alternative splicing toward functional isoforms

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月29日

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  • Alejandra Bodelón,
  • Maurice J. H. van Haaren,
  • Paula Sobrevals Alcaraz,
  • Lyanne J. P. M. Sijbers,
  • Rianne C. Scholman,
  • Lucas W. Picavet,
  • Aafke de Ligt,
  • Daphne van Ginneken,
  • Remco G. A. Erkens,
  • Harmjan R. Vos,
  • Jorg J. A. Calis,
  • Sebastiaan J. Vastert,
  • Jorg van Loosdregt

摘要

Alternative splicing is a key mechanism for expanding transcriptomic and proteomic complexity, yet its role in innate immune activation remains incompletely understood. Here, we applied Oxford Nanopore native RNA-sequencing to generate an isoform-level transcriptome of primary human monocytes before and after activation with lipopolysaccharide. We identify over 24,000 expressed isoforms, including thousands of previously unannotated variants. Activation induced widespread isoform-specific expression changes, leading to extensive isoform switching events, which were validated using matched short-read RNA-Seq. These activation-induced shifts enhanced transcript immune-regulatory functions: activated monocytes preferentially express longer, coding-competent isoforms with complete open reading frames, fewer retained introns, and increased domain complexity. By integrating matched Ribo-seq and proteomic data, we demonstrate that these isoform modulations are associated with enhanced translation of immune effector proteins. Together, our findings position alternative splicing as a dynamic and functional regulator of monocyte activation, emphasizing the need for isoform-level resolution to fully understand immune cell function.