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<p>Alternative splicing (AS) is a ubiquitous post-transcriptional regulatory mechanism, that has greatly expanded the transcriptomic and proteomic diversity in vertebrates. While gene regulation of hematopoiesis has been extensively researched in vertebrates, the functions of species- and cell lineage-specific splice variants in vertebrates are largely unknown. Here, we curate transcriptomic data on fetal hematopoietic organ development in six vertebrates and hematopoietic cell differentiation in humans and mice. To identify functional exon-skipping events among thousands of cassette exons in protein-coding genes for a specific differentiation lineage and species, we develop a machine-learning model interrogating 19 features including dynamic expression, protein structure, and evolutionary conservation, and integrate them into a single prediction score, named Functional AS Score (FAScore). Using FAScore, we identify four previously-uncharacterized functional AS events in which deletion of the AS exon leads to defects in erythropoiesis and myelopoiesis. Furthermore, we demonstrate that deletion of exon 15 of <i>TBC1D23</i> reduces erythropoiesis in mice and zebrafish through elevated binding capacity to RANBP2/RANGAP1 leading to increased SUMOylation level of <i>HDAC1</i>. Collectively, our study presents a valuable tool to identify functional exon skipping (ES) events during hematopoietic lineage commitment, and establishes a research paradigm that can be broadly applied to other biological processes.</p>

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The functional landscape of alternative splicing in hematopoietic lineage commitment

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月27日

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  • Xiao Hu,
  • Jinrui Wang,
  • Li Chen,
  • Qin Yang,
  • Manuel Tardaguila,
  • Bin Mao,
  • Shenghui Niu,
  • Zijie Xu,
  • GuiHua Wang,
  • Dan Zhang,
  • Yating Zhang,
  • Zhen Zhou,
  • Jing Luo,
  • Zhifeng He,
  • Defu Liu,
  • Chao Tang,
  • Nicole Soranzo,
  • Jing-wen Lin,
  • Da Jia,
  • Lu Chen

摘要

Alternative splicing (AS) is a ubiquitous post-transcriptional regulatory mechanism, that has greatly expanded the transcriptomic and proteomic diversity in vertebrates. While gene regulation of hematopoiesis has been extensively researched in vertebrates, the functions of species- and cell lineage-specific splice variants in vertebrates are largely unknown. Here, we curate transcriptomic data on fetal hematopoietic organ development in six vertebrates and hematopoietic cell differentiation in humans and mice. To identify functional exon-skipping events among thousands of cassette exons in protein-coding genes for a specific differentiation lineage and species, we develop a machine-learning model interrogating 19 features including dynamic expression, protein structure, and evolutionary conservation, and integrate them into a single prediction score, named Functional AS Score (FAScore). Using FAScore, we identify four previously-uncharacterized functional AS events in which deletion of the AS exon leads to defects in erythropoiesis and myelopoiesis. Furthermore, we demonstrate that deletion of exon 15 of TBC1D23 reduces erythropoiesis in mice and zebrafish through elevated binding capacity to RANBP2/RANGAP1 leading to increased SUMOylation level of HDAC1. Collectively, our study presents a valuable tool to identify functional exon skipping (ES) events during hematopoietic lineage commitment, and establishes a research paradigm that can be broadly applied to other biological processes.