Genomics

Dataset Information

297

Integrative functional genomics identifies an enhancer looping to the SOX9 gene disrupted by the 17q24.3 prostate cancer risk locus


ABSTRACT: Genome-wide association studies (GWAS) are identifying genetic predisposition to various diseases. The rs1859962 single nucleotide polymorphism (SNP) part of the 17q24.3 locus is a risk factor for prostate cancer (PCa). It defines a 130kb linkage disequilibrium (LD) block that lies in a ~2Mb gene desert area. Despite a role for the proximal SOX9 gene in PCa development, the functional biology driving the risk of this 17q24.3 risk locus is unknown. In the present study, we integrate genome-wide chromatin landscape datasets, namely epigenomes and chromatin openness from diverse cell-types to identify one PCa specific enhancer within the rs1859962 risk LD block. We reveal that this enhancer is part of a 1Mb chromatin loop with the SOX9 gene in PCa cells. The rs8072254 and rs1859961 SNPs part of this LD block map to this enhancer and impose allele-specific gene expression. The variant allele of rs1859961 directly decreases FoxA1 binding while increasing AP-1 binding compared to the reference allele. This latter is key in driving allele-specific gene expression. Together, our results demonstrate the risk associated with the PCa rs1859962 risk LD block is accounted for by multiple genetic variants mapping to a unique enhancer looping to the SOX9 oncogene. Allele-specific recruitment of the transcription factor AP-1 accounts in part for the increased enhancer activity ascribed to this PCa risk LD block. This further demonstrates that an integrative genomics approach can identify the functional biology disrupted by genetic risk-variants. Examination of histone modification H3K36me3 in the prostate cancer LNCaP cell line under DHT treatment.

ORGANISM(S): Homo sapiens  

SUBMITTER: xiaoyang zhang   Xiaoyang Zhang 

PROVIDER: E-GEOD-35829 | ArrayExpress | 2012-06-03

SECONDARY ACCESSION(S): GSE35829SRP010966PRJNA151893

REPOSITORIES: GEO, ArrayExpress, ENA

altmetric image

Publications

Integrative functional genomics identifies an enhancer looping to the SOX9 gene disrupted by the 17q24.3 prostate cancer risk locus.

Zhang Xiaoyang X   Cowper-Sal lari Richard R   Bailey Swneke D SD   Moore Jason H JH   Lupien Mathieu M  

Genome research 20120604 8


Genome-wide association studies (GWAS) are identifying genetic predisposition to various diseases. The 17q24.3 locus harbors the single nucleotide polymorphism (SNP) rs1859962 that is statistically associated with prostate cancer (PCa). It defines a 130-kb linkage disequilibrium (LD) block that lies in an ∼2-Mb gene desert area. The functional biology driving the risk associated with this LD block is unknown. Here, we integrate genome-wide chromatin landscape data sets, namely, epigenomes and ch  ...[more]

Similar Datasets

2016-02-29 | E-GEOD-73372 | ArrayExpress
2014-01-29 | E-GEOD-44592 | ArrayExpress
| GSE84273 | GEO
2010-12-26 | GSE24261 | GEO
2010-12-26 | E-GEOD-24261 | ArrayExpress
2013-01-01 | E-GEOD-35419 | ArrayExpress
2015-08-07 | E-GEOD-62023 | ArrayExpress
| GSE63693 | GEO
2007-09-01 | GSE8142 | GEO
2015-07-01 | E-GEOD-69110 | ArrayExpress