The hyperconnected 3D clique at the Ets1 locus is required for T cell function (ATAC-Seq)

The spatiotemporal control of gene-expression programs relies on selection and nuclear organization of enhancers. Despite mounting evidence on the formation of multi-enhancer hubs with extensive spatial connectivity, the functional importance of these architectural units remains elusive. Here, we generated a new mouse model and genetically perturbed a genomic locus harboring the Ets1 gene which is hyperconnected in T cells and has strong association with immune-mediated diseases. Although T cell development was intact, competence towards CD4+ T helper 1 specialization was lost in vitro and in vivo after genetic perturbation of the Ets1 locus. Extensive high-resolution molecular mapping of 3D genome organization revealed that the hyperconnectivity of the Ets1 locus controlled the expression level of Ets1 which was required for the Th1-specific genome topology. Our work illustrates the functional relevance of multi-enhancer hub formation in T cells. Overall design: ATAC-Seq