CAUSEL: An epigenome- and genome-editing pipeline for establishing function of noncoding GWAS variants

S. Spisák, Kate Lawrenson, Yanfang Fu, I. Csabai, Rebecca T. Cottman, Ji Heui Seo, Christopher Haiman, Ying Han, Romina Lenci, Qiyuan Li, Viktória Tisza, Zoltán Szállási, Zachery T. Herbert, Matthew Chabot, Mark Pomerantz, N. Solymosi, Simon A. Gayther, J. Keith Joung, Matthew L. Freedman

Research output: Contribution to journalArticle

48 Citations (Scopus)

Abstract

The vast majority of disease-associated single-nucleotide polymorphisms (SNPs) mapped by genome-wide association studies (GWASs) 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 followed by phenotypic characterization. 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 the rs339331 region possessed regulatory potential. By 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 regulatory factor 6 (RFX6) gene, increased homeobox B13 (HOXB13) binding at the rs339331 region, and increased deposition of the enhancer-associated H3K4me2 histone mark at the rs339331 region compared to lines homozygous for the 'C' protective allele. 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 that can be used to establish functional causality for noncoding sequence variants identified by GWASs.

Original languageEnglish
Pages (from-to)1357-1363
Number of pages7
JournalNature Medicine
Volume21
Issue number11
DOIs
Publication statusPublished - Nov 1 2015

Fingerprint

Genome-Wide Association Study
Single Nucleotide Polymorphism
Pipelines
Genes
Cell Line
Prostatic Neoplasms
Histone Code
Alleles
Polymorphism
Homeobox Genes
Nucleic Acid Regulatory Sequences
Nucleotides
Epigenomics
Causality
Cells
Androgens
Transcription
Transcription Factors
Genotype
Genome

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

CAUSEL : An epigenome- and genome-editing pipeline for establishing function of noncoding GWAS variants. / Spisák, S.; Lawrenson, Kate; Fu, Yanfang; Csabai, I.; Cottman, Rebecca T.; Seo, Ji Heui; Haiman, Christopher; Han, Ying; Lenci, Romina; Li, Qiyuan; Tisza, Viktória; Szállási, Zoltán; Herbert, Zachery T.; Chabot, Matthew; Pomerantz, Mark; Solymosi, N.; Gayther, Simon A.; Joung, J. Keith; Freedman, Matthew L.

In: Nature Medicine, Vol. 21, No. 11, 01.11.2015, p. 1357-1363.

Research output: Contribution to journalArticle

Spisák, S, Lawrenson, K, Fu, Y, Csabai, I, Cottman, RT, Seo, JH, Haiman, C, Han, Y, Lenci, R, Li, Q, Tisza, V, Szállási, Z, Herbert, ZT, Chabot, M, Pomerantz, M, Solymosi, N, Gayther, SA, Joung, JK & Freedman, ML 2015, 'CAUSEL: An epigenome- and genome-editing pipeline for establishing function of noncoding GWAS variants', Nature Medicine, vol. 21, no. 11, pp. 1357-1363. https://doi.org/10.1038/nm.3975
Spisák, S. ; Lawrenson, Kate ; Fu, Yanfang ; Csabai, I. ; Cottman, Rebecca T. ; Seo, Ji Heui ; Haiman, Christopher ; Han, Ying ; Lenci, Romina ; Li, Qiyuan ; Tisza, Viktória ; Szállási, Zoltán ; Herbert, Zachery T. ; Chabot, Matthew ; Pomerantz, Mark ; Solymosi, N. ; Gayther, Simon A. ; Joung, J. Keith ; Freedman, Matthew L. / CAUSEL : An epigenome- and genome-editing pipeline for establishing function of noncoding GWAS variants. In: Nature Medicine. 2015 ; Vol. 21, No. 11. pp. 1357-1363.
@article{450ac1fd9376411791a5a0b00c00ff50,
title = "CAUSEL: An epigenome- and genome-editing pipeline for establishing function of noncoding GWAS variants",
abstract = "The vast majority of disease-associated single-nucleotide polymorphisms (SNPs) mapped by genome-wide association studies (GWASs) 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 followed by phenotypic characterization. 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 the rs339331 region possessed regulatory potential. By 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 regulatory factor 6 (RFX6) gene, increased homeobox B13 (HOXB13) binding at the rs339331 region, and increased deposition of the enhancer-associated H3K4me2 histone mark at the rs339331 region compared to lines homozygous for the 'C' protective allele. 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 that can be used to establish functional causality for noncoding sequence variants identified by GWASs.",
author = "S. Spis{\'a}k and Kate Lawrenson and Yanfang Fu and I. Csabai and Cottman, {Rebecca T.} and Seo, {Ji Heui} and Christopher Haiman and Ying Han and Romina Lenci and Qiyuan Li and Vikt{\'o}ria Tisza and Zolt{\'a}n Sz{\'a}ll{\'a}si and Herbert, {Zachery T.} and Matthew Chabot and Mark Pomerantz and N. Solymosi and Gayther, {Simon A.} and Joung, {J. Keith} and Freedman, {Matthew L.}",
year = "2015",
month = "11",
day = "1",
doi = "10.1038/nm.3975",
language = "English",
volume = "21",
pages = "1357--1363",
journal = "Nature Medicine",
issn = "1078-8956",
publisher = "Nature Publishing Group",
number = "11",

}

TY - JOUR

T1 - CAUSEL

T2 - An epigenome- and genome-editing pipeline for establishing function of noncoding GWAS variants

AU - Spisák, S.

AU - Lawrenson, Kate

AU - Fu, Yanfang

AU - Csabai, I.

AU - Cottman, Rebecca T.

AU - Seo, Ji Heui

AU - Haiman, Christopher

AU - Han, Ying

AU - Lenci, Romina

AU - Li, Qiyuan

AU - Tisza, Viktória

AU - Szállási, Zoltán

AU - Herbert, Zachery T.

AU - Chabot, Matthew

AU - Pomerantz, Mark

AU - Solymosi, N.

AU - Gayther, Simon A.

AU - Joung, J. Keith

AU - Freedman, Matthew L.

PY - 2015/11/1

Y1 - 2015/11/1

N2 - The vast majority of disease-associated single-nucleotide polymorphisms (SNPs) mapped by genome-wide association studies (GWASs) 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 followed by phenotypic characterization. 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 the rs339331 region possessed regulatory potential. By 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 regulatory factor 6 (RFX6) gene, increased homeobox B13 (HOXB13) binding at the rs339331 region, and increased deposition of the enhancer-associated H3K4me2 histone mark at the rs339331 region compared to lines homozygous for the 'C' protective allele. 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 that can be used to establish functional causality for noncoding sequence variants identified by GWASs.

AB - The vast majority of disease-associated single-nucleotide polymorphisms (SNPs) mapped by genome-wide association studies (GWASs) 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 followed by phenotypic characterization. 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 the rs339331 region possessed regulatory potential. By 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 regulatory factor 6 (RFX6) gene, increased homeobox B13 (HOXB13) binding at the rs339331 region, and increased deposition of the enhancer-associated H3K4me2 histone mark at the rs339331 region compared to lines homozygous for the 'C' protective allele. 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 that can be used to establish functional causality for noncoding sequence variants identified by GWASs.

UR - http://www.scopus.com/inward/record.url?scp=84946221310&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84946221310&partnerID=8YFLogxK

U2 - 10.1038/nm.3975

DO - 10.1038/nm.3975

M3 - Article

C2 - 26398868

AN - SCOPUS:84946221310

VL - 21

SP - 1357

EP - 1363

JO - Nature Medicine

JF - Nature Medicine

SN - 1078-8956

IS - 11

ER -