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

Hengxin Liu

doi:10.1038/s41592-026-03174-y

2026-07-24

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DOI：10.1038/s41592-026-03174-y

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灵长类大脑表现出复杂的RNA可变剪接异质性，这对功能复杂性至关重要，但系统的空间异构体表征一直缺乏。我们开发了Fullscope-seq，这是一种全长单分子大视野空间转录组学测序方法，可在单细胞分辨率下进行，基于程序化连接cDNA，适用于多种长读长测序平台。将Fullscope-seq应用于猕猴大脑，我们发现数千个基因在皮质层、细胞类型和脑区之间表现出差异转录体使用（DTU）。Fullscope-seq解析了不同脑区之间的数百种主要异构体转换，并鉴定了浅层和深层皮质层之间的DTU。皮质层特异的DTU表现出细胞组成依赖性，而区域性DTU则根据细胞组成和空间背景进行调控。这些异构体变异在精神神经疾病相关基因中显著富集，并在不同平台和物种间得到保守。本研究建立了一个可扩展的空间异构体分析框架，并为理解复杂组织中的转录组多样性提供了资源。Fullscope-seq结合了空间转录组学方法（Stereo-seq）和长读长测序。该方法在大视野下以单细胞分辨率提供异构体信息，在猕猴脑切片上得到了验证。

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Nature Methods

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32.1

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BGI Research

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Lingang Laboratory

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410

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chinese academy of sciences

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