Parkinson-associated risk variant in distal enhancer of -synuclein modulates target gene expression

• Published in: Nature (London) 2016-05, Vol.533 (7601), p.95
• Main Authors: Soldner, Frank, Stelzer, Yonatan, Shivalila, Chikdu S, Abraham, Brian J, Latourelle, Jeanne C, Barrasa, M. Inmaculada, Goldmann, Johanna, Myers, Richard H, Young, Richard A, Jaenisch, Rudolf
• Format: Article
• Language: English
• Subjects: Cloning; Deregulation; Epigenetics; Gene expression; Genetic aspects; Genetic diversity; Genetic variance; Genomes; Health aspects; Membrane proteins; Parkinson disease; Parkinson's disease; Pathogenesis; Phenotypic variations; Risk factors; Stem cells; Studies; Transcription factors
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature17939

Genome-wide association studies (GWAS) have identified numerous genetic variants associated with complex diseases, but mechanistic insights are impeded by a lack of understanding of how specific risk variants functionally contribute to the underlying pathogenesis1. It has been proposed that cis-acting effects of non-coding risk variants on gene expression are a major factor for phenotypic variation of complex traits and disease susceptibility. Recent genome-scale epigenetic studies have highlighted the enrichment of GWASidentified variants in regulatory DNA elements of disease-relevant cell types2-6. Furthermore, single nucleotide polymorphism (SNP)- specific changes in transcription factor binding are correlated with heritable alterations in chromatin state and considered a major mediator of sequence-dependent regulation of gene expression7-10. Here we describe a novel strategy to functionally dissect the cisacting effect of genetic risk variants in regulatory elements on gene expression by combining genome-wide epigenetic information with clustered regularly-interspaced short palindromic repeats (CRISPR)/Cas9 genome editing in human pluripotent stem cells. By generating a genetically precisely controlled experimental system, we identify a common Parkinson's disease associated risk variant in a non-coding distal enhancer element that regulates the expression of α-synuclein (SNCA), a key gene implicated in the pathogenesis of Parkinson's disease. Our data suggest that the transcriptional deregulation of SNCA is associated with sequence-dependent binding of the brain-specific transcription factors EMX2 and NKX6-1. This work establishes an experimental paradigm to functionally connect genetic variation with disease-relevant phenotypes.