Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Spatial Congregation of STAT Binding Directs Selective Nuclear Architecture During T Cell Functional Differentiation

ABSTRACT: Although higher-order genome organization is tissue-specific, its functional relevance and mechanistic basis are poorly understood. Here we analyzed the dynamics of chromatin interactions for lineage-specific cytokine loci during T helper (Th) differentiation. The naive-to-effector transition is accompanied by a profound shift from promiscuous to highly selective and functionally enriched genome-wide contacts. Despite the establishment of divergent interactomes and global reprogramming of transcription in Th1 versus Th2 commitment, the overall expression status of the contact genes is surprisingly similar between the two lineages. Importantly, the genomic contacts are retained and strengthened precisely at DNA binding sites of the specific lineage-determining STAT transcription factor. The global aggregation of STAT binding loci from genic and non-genic regions highlights a new role for differentiation-promoting transcription factors in direct specification of higher-order nuclear architecture through interacting with regulatory regions. Such subnuclear environments have implications for efficient functioning of the mature effector lymphocytes. Nineteen arrays total: Eighteen microarrays from individual biological replicates, one microarray from a pool of two biological replicates.

ORGANISM(S): Mus musculus

SUBMITTER: Myong-Hee Sung

PROVIDER: E-GEOD-38717 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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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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Spatial Congregation of STAT Binding Directs Selective Nuclear Architecture During T Cell Functional Differentiation

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