Functional Enhancers at the Gene-Poor 8q24 Cancer-Linked Locus

被引：193

作者：

Jia, Li ^{[1
,2
]}

Landan, Gilad ^{[3
]}

Pomerantz, Mark ^{[4
]}

Jaschek, Rami ^{[3
]}

Herman, Paula ^{[4
]}

Reich, David ^{[5
]}

Yan, Chunli ^{[1
]}

Khalid, Omar ^{[1
,2
]}

Kantoff, Phil ^{[4
]}

Oh, William ^{[4
]}

Manak, J. Robert ^{[6
]}

Berman, Benjamin P. ^{[7
]}

Henderson, Brian E. ^{[1
]}

Frenkel, Baruch ^{[8
,9
]}

Haiman, Christopher A. ^{[1
]}

Freedman, Matthew ^{[4
,10
]}

Tanay, Amos ^{[3
]}

Coetzee, Gerhard A. ^{[1
,2
]}

机构：

[1] Univ So Calif, Dept Prevent Med, USC Norris Canc Ctr, Los Angeles, CA 90089 USA

[2] Univ So Calif, Dept Urol, Los Angeles, CA 90089 USA

[3] Weizmann Inst Sci, Dept Comp Sci & Appl Math, IL-76100 Rehovot, Israel

[4] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA

[5] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA

[6] Univ Iowa, Dept Biol, Iowa City, IA 52242 USA

[7] Univ So Calif, Keck Sch Med, USC Epigenome Ctr, Los Angeles, CA 90033 USA

[8] Univ So Calif, Inst Med Genet, Dept Orthoped Surg, Los Angeles, CA 90089 USA

[9] Univ So Calif, Inst Med Genet, Dept Biochem & Mol Biol, Los Angeles, CA 90089 USA

[10] Broad Inst Harvard & MIT, Cambridge, MA USA

来源：

PLOS GENETICS | 2009年 / 5卷 / 08期

关键词：

PROSTATE-CANCER; ANDROGEN RECEPTOR; HUMAN GENOME; MULTIETHNIC COHORT; TRANSCRIPTION; SIGNATURES; DISTINCT; CELLS; RISK; LINE;

D O I：

10.1371/journal.pgen.1000597

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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 nonprotein coding regions as it emerges from genome-wide association studies to better understand the genetic predisposition of complex diseases.

引用

页数：10

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