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<p>The primate brain exhibits complex RNA alternative splicing heterogeneity crucial for functional complexity, yet systematic spatial isoform characterization has been lacking. We developed Fullscope-seq, a full-length single-molecule large field-of-view spatial transcriptomics sequencing method at single-cell resolution, based on programmed concatenation cDNA for multiple long-read sequencing platforms. Applying Fullscope-seq to the macaque brain, we uncovered thousands of genes exhibiting differential transcript usage (DTU) across cortical layers, cell types and brain regions. Fullscope-seq resolved hundreds of major isoform switches across distinct brain regions and identified DTUs between superficial and deep cortical layers. Cortical layer-specific DTUs showed cell-composition dependence, whereas regional DTUs were regulated according to both cellular composition and spatial contexts. These isoform variations showed substantial enrichment for neuropsychiatric disorder-associated genes and were conserved across platforms and species. Our study establishes a scalable framework for spatial isoform analysis and provides a resource for understanding transcriptomic diversity in complex tissues.</p>

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Full-length single-cell spatial transcriptomics reveals spatial and cell-type-specific transcript isoforms in the primate brain

  • 期刊论文

  • 发表日期：

    2026年7月24日

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  • Hengxin Liu,
  • Yanhong Hong,
  • Yao Santo Zhang,
  • Liyuan Xi,
  • Huiying Yan,
  • Yuxuan Liu,
  • Qianqian Yang,
  • Xing Sun,
  • Shouliang Guan,
  • Zan Chen,
  • Yu Feng,
  • Tao Zeng,
  • Juan Meng,
  • Sha Liao,
  • Nini Yuan,
  • Zhen Liu,
  • Chao Li,
  • Zhiyong Liu,
  • Lei Han,
  • Zhiming Shen,
  • Ao Chen,
  • Yidi Sun,
  • Yuliang Dong,
  • Longqi Liu,
  • Chengyu Li,
  • Wu Wei

摘要

The primate brain exhibits complex RNA alternative splicing heterogeneity crucial for functional complexity, yet systematic spatial isoform characterization has been lacking. We developed Fullscope-seq, a full-length single-molecule large field-of-view spatial transcriptomics sequencing method at single-cell resolution, based on programmed concatenation cDNA for multiple long-read sequencing platforms. Applying Fullscope-seq to the macaque brain, we uncovered thousands of genes exhibiting differential transcript usage (DTU) across cortical layers, cell types and brain regions. Fullscope-seq resolved hundreds of major isoform switches across distinct brain regions and identified DTUs between superficial and deep cortical layers. Cortical layer-specific DTUs showed cell-composition dependence, whereas regional DTUs were regulated according to both cellular composition and spatial contexts. These isoform variations showed substantial enrichment for neuropsychiatric disorder-associated genes and were conserved across platforms and species. Our study establishes a scalable framework for spatial isoform analysis and provides a resource for understanding transcriptomic diversity in complex tissues.