title: Decoding the role of regulatory element polymorphisms in complex disease.
abstract: Genetic variation in gene regulatory elements contributes to diverse human diseases, ranging from rare and severe developmental defects to common and complex diseases such as obesity and diabetes. Early examples of regulatory mechanisms of human diseases involve large chromosomal rearrangements that change the regulatory connections within the genome. Single nucleotide variants in regulatory elements can also contribute to disease, potentially via demonstrated associations with changes in transcription factor binding, enhancer activity, post-translational histone modifications, long-range enhancer-promoter interactions, or RNA polymerase recruitment. Establishing causality between non-coding genetic variants, gene regulation, and disease has recently become more feasible with advances in genome-editing and epigenome-editing technologies. As establishing causal regulatory mechanisms of diseases becomes routine, functional annotation of target genes is likely to emerge as a major bottleneck for translation into patient benefits. In this review, we discuss the history and recent advances in understanding the regulatory mechanisms of human disease, and new challenges likely to be encountered once establishing those mechanisms becomes rote.
authors.affiliation: Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, United States; Department of Biostatistics & Bioinformatics, and Center for Genomic & Computational Biology, Duke University Medical Center, Durham, NC 27710, United States.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Vockley
authors.affiliation: Department of Biostatistics & Bioinformatics, and Center for Genomic & Computational Biology, Duke University Medical Center, Durham, NC 27710, United States.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Barrera
authors.affiliation: Department of Biostatistics & Bioinformatics, and Center for Genomic & Computational Biology, Duke University Medical Center, Durham, NC 27710, United States. Electronic address: tim.reddy@duke.edu.
authors.forename: Timothy E
authors.initials: TE
authors.lastname: Reddy
mesh_terms: D012321:DNA-Directed RNA Polymerases / Q000235:genetics; D004742:Enhancer Elements, Genetic; D005786:Gene Expression Regulation / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D015894:Genome, Human / Q000235:genetics*; D006801:Humans; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics*
chemical_list: D012321:DNA-Directed RNA Polymerases