Functional enhancers at the gene-poor 8q24 cancer-linked locus.
Multiple discrete regions at 8q24 were recently shown to contain alleles that predispose to many cancers including prostate, breast, and colon. These regions are far from any annotated gene and their biological activities have been unknown. Here we profiled a 5-megabase chromatin segment encompassing all the risk regions for RNA expression, histone modifications, and locations occupied by RNA polymerase II and androgen receptor (AR). This led to the identification of several transcriptional enhancers, which were verified using reporter assays. Two enhancers in one risk region were occupied by AR and responded to androgen treatment; one contained a single nucleotide polymorphism (rs11986220) that resides within a FoxA1 binding site, with the prostate cancer risk allele facilitating both stronger FoxA1 binding and stronger androgen responsiveness. The study reported here exemplifies an approach that may be applied to any risk-associated allele in non-protein coding regions as it emerges from genome-wide association studies to better understand the genetic predisposition of complex diseases.
Jia
Li
L
USC/Norris Cancer Center, Department of Preventive Medicine, University of Southern California, Los Angeles, CA, USA.
Landan
Gilad
G
Pomerantz
Mark
M
Jaschek
Rami
R
Herman
Paula
P
Reich
David
D
Yan
Chunli
C
Khalid
Omar
O
Kantoff
Phil
P
Oh
William
W
Manak
J Robert
JR
Berman
Benjamin P
BP
Henderson
Brian E
BE
Frenkel
Baruch
B
Haiman
Christopher A
CA
Freedman
Matthew
M
Tanay
Amos
A
Coetzee
Gerhard A
GA
D002460:Cell Line; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics* / Q000378:metabolism; D004742:Enhancer Elements, Genetic; D055106:Genome-Wide Association Study; D006801:Humans; D009369:Neoplasms / Q000235:genetics*
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