Gene Regulatory Circuitry Of Disease Risk And Progression

Author : Olivia G Corradin
Publisher :
ISBN 13 :
Total Pages : 0 pages
Book Rating : 4.:/5 (927 download)

DOWNLOAD NOW!

Download or read book Impact of DNA Variants in the Regulatory Circuitry of Gene Expression in Human Disease written by Olivia G Corradin and published by . This book was released on 2015 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: Transcriptional enhancer elements are essential in the establishment and maintenance of gene expression programs that define cellular identity and function. DNA variants that predispose to common disease, identified by genome-wide association studies (GWAS), frequently lie in enhancer elements. Interpreting the impact of DNA variants on enhancer function and transcriptional output is key to determining the role of the disease-associated variants in the pathogenesis of disease. Here we present PreSTIGE (Predicting Specific Tissue Interactions of Genes and Enhancers), a method that identifies the specific gene targets of enhancers, and apply this methodology to delineate the impact of disease-associated variants on enhancer function. We demonstrate that for six autoimmune traits, GWAS association signals often arise from multiple polymorphisms in linkage disequilibrium (LD) that map to clusters of active enhancer elements. This result suggests a "multiple enhancer variant" hypothesis, in which several variants in LD alter enhancer function and cooperatively affect transcript levels. Multiple enhancer variants within a given locus are determined by PreSTIGE to target the same gene. To address the question of whether additional variants within a target gene's regulatory circuitry can alter the transcriptional effect of the locus, we identified variants that are inherited independently of known GWAS risk loci and interact with disease-associated variants. The interacting SNPs lie in enhancer elements that are constituents of the regulatory circuitry of the same gene. These variants, termed "outside variants" functionally modify the effect of the risk variants on target transcript levels and ultimately alter clinical risk. To further our understanding of the regulatory circuitry that dictates gene expression levels, we evaluated how transcriptional control is established and altered during early embryogenesis. We found that the regulatory circuitry of genes expressed similarly in two sequential stages of pluripotency undergoes extensive rewiring as naive stem cells transition into pluripotent stem cells primed for differentiation. This rewiring appropriates transcriptional control to a new set of enhancers, which we term "seed" enhancers. Seed enhancers are more frequently utilized in downstream somatic tissues and often expand into enhancer clusters. Taken together, these results demonstrate how the multiple enhancer elements that comprise the regulatory circuitry of a gene cooperatively control transcription in normal development and human disease. Our results indicate that the impact of disease-associated loci is frequently reliant on the combinatorial effects of multiple variants that perturb enhancers within the same regulatory circuit.