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

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.