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
Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA.
Center for Neurogenetics, Weill Cornell Medicine, New York, NY, USA.
Nat Biotechnol. 2025 Jul 22. doi: 10.1038/s41587-025-02734-5.
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.
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。在这里，我们结合了单细胞异构体RNA测序和转座酶可及染色质分析（ScISOr-ATAC），以研究人类和恒河猴冷冻皮质组织样本中单个细胞内这些模式之间的相关性。应用先前定义的四种“细胞状态”（其中每个基因的转录组和染色质可及性是耦合或解耦的），我们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状态不同。我们还使用ScISOr-ATAC来测量跨脑细胞类型、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特异性的剪接和染色质可及性。在人类和猕猴的前额叶皮质中，一种分子模式中的强烈进化差异并不一定意味着另一种模式中的强烈差异。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均表现出高度失调。
