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

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.