Long-Range Transcriptional Control of the Il2 Gene by an Intergenic Enhancer

Abstract

ABSTRACT Interleukin-2 (IL-2) is a potent cytokine with roles in both immunity and tolerance. Genetic studies in humans and mice demonstrate a role for Il2 in autoimmune disease susceptibility, and for decades the proximal Il2 upstream regulatory region has served as a paradigm of tissue-specific, inducible gene regulation. In this study, we have identified a novel long-range enhancer of the Il2 gene located 83 kb upstream of the transcription start site. This element can potently enhance Il2 transcription in recombinant reporter assays in vitro , and the native region undergoes chromatin remodeling, transcribes a bidirectional enhancer RNA, and loops to physically interact with the Il2 gene in vivo in a CD28-dependent manner in CD4 + T cells. This cis regulatory element is evolutionarily conserved and is situated near a human single-nucleotide polymorphism (SNP) associated with multiple autoimmune disorders. These results indicate that the regulatory architecture of the Il2 locus is more complex than previously appreciated and suggest a novel molecular basis for the genetic association of Il2 polymorphism with autoimmune disease.