The 3D enhancer network of the developing T cell genome is controlled by SATB1 [ATAC-seq]

Mechanisms of tissue-specific gene expression regulation, particularly via spatial coordination of gene promoters and their regulatory elements are poorly understood. Here we investigated the 3D genome organization of developing murine T cells. We identified a tissue-specific genome organizer SATB1 as a factor enriched at the anchors of promoter-enhancer chromatin loops. To unravel its functions in T cells, we generated Satb1fl/flCd4-Cre+ (Satb1 cKO) conditional knockout animals. Satb1 cKO animals suffer from severe autoimmunity so we sought to investigate a potential link between the autoimmunity and putatively deregulated nuclear architecture caused by SATB1 depletion. This series of ATAC-Seq experiments is a part of SuperSeries including also RNA-Seq, Hi-C and HiChIP experiments to fully understand the deregulation of Satb1 cKO thymocytes and to unravel the roles of SATB1 in T cell chromatin organization. ATAC-Seq experiments supported the repressive nature of Satb1 cKO nuclear environment and together with the other datasets it showed that SATB1 functions primarily as an activator. SATB1 mediates promoter-enhancer chromatin loops affecting a number of master regulator genes whose deregulation in knockout animals may comprise a cell-intrinsic mechanism of the autoimmunity. Our findings indicate a possible existence of a special class of genome organizers controlling tissue and/or time-specific transcriptional programs via spatial chromatin arrangements that are complementary to the function of conventional and ubiquitously expressed genome organizers. Overall design: Three biological replicates from each wild type and conditional knockout Satb1fl/flCd4-Cre+ mice were analyzed. ATAC-Seq libraries were prepared from viable thymocytes using the Omni-ATAC protocol.