RESUMEN
Genome-wide association studies (GWASs) have revealed 59 genomic loci associated with type 1 diabetes (T1D). Functional interpretation of the SNPs located in the noncoding region of these loci remains challenging. We perform epigenomic profiling of two enhancer marks, H3K4me1 and H3K27ac, using primary TH1 and TREG cells isolated from healthy and T1D subjects. We uncover a large number of deregulated enhancers and altered transcriptional circuitries in both cell types of T1D patients. We identify four SNPs (rs10772119, rs10772120, rs3176792, rs883868) in linkage disequilibrium (LD) with T1D-associated GWAS lead SNPs that alter enhancer activity and expression of immune genes. Among them, rs10772119 and rs883868 disrupt the binding of retinoic acid receptor α (RARA) and Yin and Yang 1 (YY1), respectively. Loss of binding by YY1 also results in the loss of long-range enhancer-promoter interaction. These findings provide insights into how noncoding variants affect the transcriptomes of two T-cell subtypes that play critical roles in T1D pathogenesis.
Asunto(s)
Diabetes Mellitus Tipo 1 , Elementos de Facilitación Genéticos , Polimorfismo de Nucleótido Simple , Receptor alfa de Ácido Retinoico , Linfocitos T Reguladores/inmunología , Células TH1/inmunología , Factor de Transcripción YY1 , Preescolar , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/inmunología , Diabetes Mellitus Tipo 1/patología , Epigenómica , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Lactante , Células Jurkat , Masculino , Receptor alfa de Ácido Retinoico/genética , Receptor alfa de Ácido Retinoico/inmunología , Factores de Riesgo , Linfocitos T Reguladores/patología , Células TH1/patología , Factor de Transcripción YY1/genética , Factor de Transcripción YY1/inmunologíaRESUMEN
The present study extends an earlier report that retinoic acid (RA) down-regulates IgE Ab synthesis in vitro. Here, we show the suppressive activity of RA on IgE production in vivo and its underlying mechanisms. We found that RA down-regulated IgE class switching recombination (CSR) mainly through RA receptor α (RARα). Additionally, RA inhibited histone acetylation of germ-line ε (GL ε) promoter, leading to suppression of IgE CSR. Consistently, serum IgE levels were substantially elevated in vitamin A-deficient (VAD) mice and this was more dramatic in VAD-lecithin:retinol acyltransferase deficient (LRAT-/-) mice. Further, serum mouse mast cell protease-1 (mMCP-1) level was elevated while frequency of intestinal regulatory T cells (Tregs) were diminished in VAD LRAT-/- mice, reflecting that deprivation of RA leads to allergic immune response. Taken together, our results reveal that RA has an IgE-repressive activity in vivo, which may ameliorate IgE-mediated allergic disease.