CAUSEL: An epigenome and genome editing pipeline for establishing function of non-coding GWAS variants
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Author
Spisak, Sandor
Lawrenson, Kate
Fu, Yanfang
Csabai, Istvan
Haiman, Christopher
Han, Ying
Seo, Ji-Heui
Lenci, Romina
Li, Qiyuan
Tisza, Viktoria
Szallasi, Zoltan
Herbert, Zachery T.
Chabot, Matthew
Pomerantz, Mark
Solymosi, Norbert
Gayther, Simon
Joung, J. Keith
Freedman, Matthew L.
Note: Order does not necessarily reflect citation order of authors.
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https://doi.org/10.1038/nm.3975Metadata
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Spisak, S., K. Lawrenson, Y. Fu, I. Csabai, R. T. Cottman, C. Haiman, Y. Han, et al. 2016. “CAUSEL: An epigenome and genome editing pipeline for establishing function of non-coding GWAS variants.” Nature medicine 21 (11): 1357-1363. doi:10.1038/nm.3975. http://dx.doi.org/10.1038/nm.3975.Abstract
The vast majority of disease-associated single nucleotide polymorphisms (SNPs) mapped by genome-wide association studies (GWAS) are located in the non-protein coding genome, but establishing the functional and mechanistic roles of these sequence variants has proven challenging. Here, we describe a general pipeline in which candidate functional SNPs are first evaluated by fine-mapping, epigenomic profiling, and epigenome editing and then interrogated for causal function by using genome editing to create isogenic cell lines. To validate this approach, we analyzed the 6q22.1 prostate cancer risk locus and identified rs339331 as the top scoring SNP. Epigenome editing confirmed that rs339331 possessed regulatory potential. Using transcription activator-like effector nuclease (TALEN)-mediated genome-editing, we created a panel of isogenic 22Rv1 prostate cancer cell lines representing all three genotypes (TT, TC, CC) at rs339331. Introduction of the “T” risk allele increased transcription of the RFX6 gene, increased HOXB13 binding at the rs339331 region, and increased deposition of the enhancer-associated H3K4me2 histone mark at the rs339331 region. The cell lines also differed in cellular morphology and adhesion, and pathway analysis of differentially expressed genes suggested an influence of androgens. In summary, we have developed and validated a widely accessible approach to establish functional causality for non-coding sequence variants identified by GWAS.Other Sources
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4746056/pdf/Terms of Use
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