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High-resolution spatial multi-omics reveals cell-type specific nuclear compartments

ABSTRACT: 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 organization. Understanding nuclear organization and its role in gene expression requires identifying the molecular constituents of subnuclear structures and mapping their associations with specific genomic loci and their transcriptional levels in individual cells, within complex tissues. Here, we introduce two-layer DNA seqFISH+, which allows simultaneous mapping of 100,049 genomic loci, together with nascent transcriptome for 17,856 genes and a diverse set of immunofluorescently labeled subnuclear structures all in single cells in both cell lines and complex tissues. These data enable imaging-based chromatin profiling of diverse subnuclear markers and capture changes in chromatin organization at genomic scales from 100–200 kb to approximately 1 Mb, depending on the subnuclear marker and DNA locus. Using multi-omics datasets in the adult mouse cerebellum, we showed that repressive chromatin regions are more variable by cell type than active regions across the genome. We also discovered RNA polymerase II (RNAPII)-enriched foci were locally associated with long, cell-type specific genes (> 200kb), in a manner distinct from nuclear speckles. Further, our analysis revealed that cell-type specific facultative and constitutive heterochromatin regions marked by H3K27me3 and 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 and chromatin marks, associated genomic loci, and their impacts on gene regulation, directly within complex tissues.

ORGANISM(S): Mus musculus

PROVIDER: GSE248631 | GEO | 2024/12/21

REPOSITORIES: GEO

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Project description:The spatial organization of genes in the interphase nucleus plays an important role in establishment and regulation of gene expression. Contradicting results have been reported to date, with little consensus about the dynamics of nuclear organization and the features of the contact loci. In this study we investigated the properties and dynamics of genomic loci that are in contact with glucocorticoid receptor (GR)-responsive loci. We took a systematic approach, combining genome-wide interaction profiling by the chromosome conformation capture-on-chip (4C) technology with expression, protein occupancy, and chromatin accessibility profiles. This approach allowed a comprehensive analysis of how distinct features of the linear genome are organized in the three-dimensional nuclear space in the context of rapid gene regulation. We found that the transcriptional response to GR occurs without dramatic nuclear reorganization. Moreover, contrary to the view of transcription-driven organization, even genes with opposite transcriptional responses co-localize. Regions contacting GR-regulated genes are not particularly enriched for GR-regulated loci or for any functional group of genes, suggesting that these subnuclear environments are not organized to respond to a specific factor. The contact regions are, however, highly enriched for DNaseI hypersensitive sites which represent the entire cell type-specific regulatory sites. These findings indicate that the nucleus is pre-organized in a conformation allowing rapid transcriptional reprogramming, and suggest that a major force in shaping genome architecture is the repertoire of chromatin binding factors. Numerous open chromatin loci may be arranged in nuclear domains that are poised to respond to diverse signals in general, and to permit efficient gene regulation. Fourteen arrays total: Eight microarrays from individual biological replicates, and six microarrays each from a pool of two biological replicates. This submission represents the chromosome conformation capture-on-chip component of the study. The expression data are included in GSE26189.

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High-resolution spatial multi-omics reveals cell-type specific nuclear compartments

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