The transcription factor STAT5 binds to distinct super-enhancer sites and controlsLrrc32expression in a prominent autoimmune and allergic disease risk locus

Summary Genetic variants associated with diseases are enriched in genomic sequences linked to regulatory regions, such as enhancers, super-enhancers and possibly repressors, that control nearby and distant genes. A known allergic and autoimmune risk locus at chromosome 11q13.5 1,2 is associated with the LRRC32 gene, which encodes GARP, a protein critical for TGF-β delivery 3 . This region coincides with a candidate enhancer that was predicted by the presence of activating chromatin marks and contains a polymorphism significantly associated with GARP expression on CD4 + CD127 - CD25 + T reg cells 4 . In the mouse, binding of the cytokine-induced transcription factor STAT5 was detected at two sites within the expansive candidate enhancer region and a 2.3 kb deletion resulted in reduced Lrrc32 expression 4 . However, a clear definition of the enhancer units controlled by STAT5 and a functional understanding of STAT5 in the regulation of Lrrc32 are needed. Here we use high-resolution ChIP-seq and identify three STAT5 binding sites within the Lrrc32 super-enhancer, one shared between T reg cells and mammary epithelium and one specific to each respective cell type. Using mice that express only 10% of normal STAT5 levels we demonstrate the defining contribution of STAT5 in the activation of the Lrrc32 super-enhancer.