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

Nature (London), 2016-05, Vol.533 (7601), p.95-99 [Peer Reviewed Journal]

ISSN: 0028-0836 ;EISSN: 1476-4687 ;DOI: 10.1038/nature17939 ;PMID: 27096366

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Title:
Parkinson-associated risk variant in distal enhancer of α-synuclein modulates target gene expression
Author: 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
Subjects: Alleles ; alpha-Synuclein - genetics ; Brain - metabolism ; CRISPR-Cas Systems - genetics ; Enhancer Elements, Genetic - genetics ; Epigenesis, Genetic - genetics ; Gene Expression Regulation ; Genetic Engineering ; Genetic Predisposition to Disease - genetics ; Genome, Human - genetics ; Homeodomain Proteins - metabolism ; Humans ; Models, Genetic ; Parkinson Disease - genetics ; Pluripotent Stem Cells - metabolism ; Risk ; Transcription Factors - metabolism
Is Part Of: Nature (London), 2016-05, Vol.533 (7601), p.95-99
Description: 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 pathogenesis. 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 GWAS-identified variants in regulatory DNA elements of disease-relevant cell types. 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 expression. Here we describe a novel strategy to functionally dissect the cis-acting 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.
Publisher: England
Language: English
Identifier: ISSN: 0028-0836
EISSN: 1476-4687
DOI: 10.1038/nature17939
PMID: 27096366
Source: ProQuest One Psychology
MEDLINE
ProQuest Central

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

ISSN: 0028-0836 ;EISSN: 1476-4687 ;DOI: 10.1038/nature17939 ;PMID: 27096366

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