Spatial multi-omics reveals cell-type-specific nuclear compartments

• 成果类型: Article
• 署名作者: Takei, Yodai; Yang, Yujing; White, Jonathan; Goronzy, Isabel N.; Yun, Jina; Prasad, Meera; Ombelets, Lincoln J.; Schindler, Simone; Bhat, Prashant; Guttman, Mitchell; Cai, Long
• 署名单位: California Institute of Technology; University of California System; University of California Los Angeles; University of California Los Angeles Medical Center; David Geffen School of Medicine at UCLA; Harvard University; Harvard University Medical Affiliates; Dana-Farber Cancer Institute; Washington University (WUSTL)
• 刊物名称: Nature
• ISSN/ISSBN: 0028-3518
• DOI: 10.1038/s41586-025-08838-x
• 发表日期: 2025-05-22
• 关键词: genome architecture; gene; ORGANIZATION; chromatin; transcription; heterochromatin; DYNAMICS; reorganization; association; domains

摘要

The mammalian nucleus is compartmentalized by diverse subnuclear structures. These subnuclear structures, marked by nuclear bodies and histone modifications, are often cell-type specific and affect gene regulation and 3D genome organization1, 2-3. Understanding their relationships rests on identifying the molecular constituents of subnuclear structures and mapping their associations with specific genomic loci and transcriptional levels in individual cells, all in complex tissues. Here, we introduce two-layer DNA seqFISH+, which enables simultaneous mapping of 100,049 genomic loci, together with the nascent transcriptome for 17,856 genes and subnuclear structures in single cells. These data enable imaging-based chromatin profiling of diverse subnuclear markers and can capture their changes at genomic scales ranging from 100-200 kilobases to approximately 1 megabase, depending on the marker and DNA locus. By using multi-omics datasets in the adult mouse cerebellum, we showed that repressive chromatin regions are more variable by cell type than are active regions across the genome. We also discovered that RNA polymerase II-enriched foci were locally associated with long, cell-type-specific genes (bigger than 200 kilobases) in a manner distinct from that of nuclear speckles. Furthermore, our analysis revealed that cell-type-specific regions of heterochromatin marked by histone H3 trimethylated at lysine 27 (H3K27me3) and histone H4 trimethylated at lysine 20 (H4K20me3) are enriched at specific genes and gene clusters, respectively, and shape radial chromosomal positioning and inter-chromosomal interactions in neurons and glial cells. Together, our results provide a single-cell high-resolution multi-omics view of subnuclear structures, associated genomic loci and their effects on gene regulation, directly within complex tissues.