Nature Communications · 2016 · 126 citations · 55 references
Life SciencesGeneticsImmunologyGene ExpressionImmunogeneticsMolecular ImmunologyCytokine BiologyEnhancer ArchitectureEnhancer FunctionGenetic Susceptibility To AutoimmunityImmune Gene RegulationT Cell BiologyCtcf Binding SitesDisease-specific Risk AllelesEnhancer-mediated Immune RegulationGenetic Risk VariantsImmune Regulatory Gene VariantsInterleukin-2 Gene VariantsRisk Gene VariantsTranscription Factor Variants
Abstract Asthma and autoimmune disease susceptibility has been strongly linked to genetic variants in the 17q21 haploblock that alter the expression of ORMDL3 ; however, the molecular mechanisms by which these variants perturb gene expression and the cell types in which this effect is most prominent are unclear. We found several 17q21 variants overlapped enhancers present mainly in primary immune cell types. CD4 + T cells showed the greatest increase (threefold) in ORMDL3 expression in individuals carrying the asthma-risk alleles, where ORMDL3 negatively regulated interleukin-2 production. The asthma-risk variants rs4065275 and rs12936231 switched CTCF-binding sites in the 17q21 locus, and 4C-Seq assays showed that several distal cis -regulatory elements upstream of the disrupted ZPBP2 CTCF-binding site interacted with the ORMDL3 promoter region in CD4 + T cells exclusively from subjects carrying asthma-risk alleles. Overall, our results suggested that T cells are one of the most prominent cell types affected by 17q21 variants.
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An integrated encyclopedia of DNA elements in the human genome
A 3D Map of the Human Genome at Kilobase Resolution Reveals Principles of Chromatin Looping
Suhas S.P. Rao, Miriam Huntley, Neva C. Durand et al. · Cell · 2014 · 9.9K citations · Full text
An integrated map of genetic variation from 1,092 human genomes