美国威尔康奈尔医学院Hagen U. Tilgner课题组在研究中取得进展。他们研制了跨脑细胞类型、区域和疾病状态的染色质-转录组和剪接组合单细胞谱。这一研究成果于2025年7月22日发表在国际顶尖学术期刊《自然—生物技术》上。

在这里，课题组结合单细胞异构体RNA测序和转座酶可及染色质测定（ScISOr-ATAC）来研究人类和恒河猴冷冻皮质组织样本中单细胞中这些模式之间的相关性。应用先前对每个基因的转录组和染色质可及性耦合或解耦的“细胞状态”的定义，小组证明了在同一细胞类型中，一种细胞状态下的剪接模式可能与另一种细胞状态下的剪接模式不同。

该研究团队还将ScISOr-ATAC用于测量脑细胞类型、皮质区域和物种（猕猴和人类）以及阿尔茨海默病中染色质和剪接的相关性。在猕猴中，一些兴奋性神经元亚型表现出脑区域特异性剪接和染色质可及性。在人类和猕猴前额叶皮层中，一种分子形态的强烈进化分化并不一定意味着另一种分子形态的强烈分化。最后，在阿尔茨海默病中，少突胶质细胞在染色质和剪接方面都表现出高度失调。

据介绍，在冷冻组织中同时测量剪接和染色质可及性仍然具有挑战性。

附：英文原文

Title: Combined single-cell profiling of chromatin–transcriptome and splicing across brain cell types, regions and disease state

Author: Hu, Wen, Foord, Careen, Hsu, Justine, Fan, Li, Corley, Michael J., Lanjewar, Samantha N., Xu, Siwei, Belchikov, Natan, He, Yi, Pang, Alina P. S., Bhatia, Tarun N., Jarroux, Julien, Joglekar, Anoushka, Milner, Teresa A., Ndhlovu, Lishomwa C., Zhang, Jing, Butelman, Eduardo, Sloan, Steven A., Lee, Virginia M. Y., Gan, Li, Tilgner, Hagen U.

Issue&Volume: 2025-07-22

Abstract: Measuring splicing and chromatin accessibility simultaneously in frozen tissues remains challenging. Here we combined single-cell isoform RNA sequencing and assay for transposase accessible chromatin (ScISOr–ATAC) to interrogate the correlation between these modalities in single cells in human and rhesus macaque frozen cortical tissue samples. Applying a previous definition of four ‘cell states’ in which the transcriptome and chromatin accessibility are coupled or decoupled for each gene, we demonstrate that splicing patterns in one cell state can differ from those of another state within the same cell type. We also use ScISOr–ATAC to measure the correlation of chromatin and splicing across brain cell types, cortical regions and species (macaque and human) and in Alzheimer’s disease. In macaques, some excitatory neuron subtypes show brain-region-specific splicing and chromatin accessibility. In human and macaque prefrontal cortex, strong evolutionary divergence in one molecular modality does not necessarily imply strong divergence in another modality. Finally, in Alzheimer’s disease, oligodendrocytes show high dysregulation in both chromatin and splicing.

DOI: 10.1038/s41587-025-02734-5

Source: https://www.nature.com/articles/s41587-025-02734-5