10x Genomics

Amazing work from Wen Hu, Hagen Tilgner and the team at Weill Cornell Medicine exploring the molecular complexity of brain cell types across species, regions and disease. ScISOr–ATAC combines Oxford Nanopore ultra-rich sequencing with single-cell ATAC and 10x cDNA barcoding—unlocking joint multiomic readouts directly from frozen tissue. The challenge: Can chromatin accessibility and RNA splicing be measured simultaneously in frozen brain tissue—resolving how gene regulation and isoform diversity interact across cell types, cortical regions, species, and Alzheimer’s disease? What they did: The team developed ScISOr–ATAC, a multimodal protocol to simultaneously measure chromatin accessibility and full-length isoform expression in the same single nuclei from human and macaque brain. They profiled over 19 human PFC samples (AD and control) and 4 macaque PFC and visual cortex samples, identifying how chromatin and splicing interplay differs between: Cortical regions Cell subtypes (especially excitatory neurons) Species (human vs macaque) Healthy and Alzheimer’s disease states Why it matters: This is one of the first large-scale demonstrations that splicing decisions are frequently tied to chromatin–transcription cell states, and that modalities can diverge sharply between species and in disease. It highlights the necessity of multimodal resolution—especially for understanding glial dysregulation in AD and species-specific divergence in neuron subtypes. Key findings: Splicing and chromatin decouple across regions: In macaques, L3–L5/L6 IT_RORB neurons showed strong brain-region-specific splicing, while L2–L4 IT_CUX2.RORB neurons had the most chromatin divergence. Divergence across species is cell-type-specific: Astrocytes showed the largest chromatin changes between human and macaque, whereas L2–L3 IT_NRGN.CBLN2 neurons showed high species-specific splicing. In Alzheimer’s disease, oligodendrocytes exhibited the strongest dysregulation in both chromatin and splicing, including loss of a regulatory exon in ZNF711, a gene linked to X-linked intellectual disability. Cell state matters: 55% of species-specific exons and a substantial proportion of AD-associated splicing changes were explained by distinct chromatin–transcriptome “cell states”. Legacy short-read methods? They cannot simultaneously resolve: Splice isoform usage and chromatin accessibility in the same nucleus Cell-state-resolved isoform shifts, particularly across primate species or in diseased tissue Exon-level inclusion variability within defined chromatin–transcription states Moreover, short-read data lacks the molecule-level phasing necessary to relate chromatin state to full isoform identity in complex tissues. The switch is ON. Daniel Garalde, Stephanie Abernathy Renner, Sissel Juul, 10x Genomics, Oxford Nanopore Technologies https://lnkd.in/e-h666Yi