title: Multiple single nucleotide polymorphisms in the first intron of the IL2RA gene affect transcription factor binding and enhancer activity.
abstract: IL2RA gene encodes the alpha subunit of a high-affinity receptor for interleukin-2 which is expressed by several distinct populations of lymphocytes involved in autoimmune processes. A large number of polymorphic alleles of the IL2RA locus are associated with the development of various autoimmune diseases. With bioinformatics analysis we the dissected the first intron of the IL2RA gene and selected several single nucleotide polymorphisms (SNPs) that may influence the regulation of the IL2RA gene in cell types relevant to autoimmune pathology. We described five enhancers containing the selected SNPs that stimulated activity of the IL2RA promoter in a cell-type specific manner, and tested the effect of specific SNP alleles on activity of the respective enhancers (E1 to E5, labeled according to the distance to the promoter). The E4 enhancer with minor T variant of rs61839660 SNP demonstrated reduced activity due to disrupted binding of MEF2A/C transcription factors (TFs). Neither rs706778 nor rs706779 SNPs, both associated with a number of autoimmune diseases, had any effect on the activity of the enhancer E2. However, rare variants of several SNPs (rs139767239, rs115133228, rs12722502, rs12722635) genetically linked to either rs706778 and/or rs706779 significantly influenced the activity of E1, E3 and E5 enhancers, presumably by disrupting EBF1, GABPA and ELF1 binding sites.
authors.affiliation: Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia.
authors.forename: Anton M
authors.initials: AM
authors.lastname: Schwartz
authors.affiliation: Moscow Institute of Physics and Technology, Department Molecular and Biological Physics, Moscow, Russia.
authors.forename: Denis E
authors.initials: DE
authors.lastname: Demin
authors.affiliation: Vavilov Institute of General Genetics, Russian Academy of Sciences, Moscow, Russia.
authors.forename: Ilya E
authors.initials: IE
authors.lastname: Vorontsov
authors.affiliation: Vavilov Institute of General Genetics, Russian Academy of Sciences, Moscow, Russia.
authors.forename: Artem S
authors.initials: AS
authors.lastname: Kasyanov
authors.affiliation: Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia.
authors.forename: Lidia V
authors.initials: LV
authors.lastname: Putlyaeva
authors.affiliation: Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia.
authors.forename: Karina A
authors.initials: KA
authors.lastname: Tatosyan
authors.affiliation: Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia; Vavilov Institute of General Genetics, Russian Academy of Sciences, Moscow, Russia.
authors.forename: Ivan V
authors.initials: IV
authors.lastname: Kulakovskiy
authors.affiliation: Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia; Moscow Institute of Physics and Technology, Department Molecular and Biological Physics, Moscow, Russia; Faculty of Biology, Lomonosov Moscow State University, Moscow, Russia. Electronic address: kuprash@eimb.ru.
authors.forename: Dmitry V
authors.initials: DV
authors.lastname: Kuprash
mesh_terms: D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology; D002460:Cell Line; D004742:Enhancer Elements, Genetic; D020022:Genetic Predisposition to Disease; D006801:Humans; D053645:Interleukin-2 Receptor alpha Subunit / Q000235:genetics*; D007438:Introns; D019169:Jurkat Cells; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
chemical_list: C508017:IL2RA protein, human; D053645:Interleukin-2 Receptor alpha Subunit; D014157:Transcription Factors
keywords: Autoimmune disease; Enchancer; IL2RA; SNP; Transcription factor