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Prostate cancer risk locus at 8q24 as a regulatory hub by physical interactions with multiple genomic loci across the genome. Hum Mol Genet 2015 Jan 01;24(1):154-66

Date

08/26/2014

Pubmed ID

25149474

Pubmed Central ID

PMC4262497

DOI

10.1093/hmg/ddu426

Scopus ID

2-s2.0-84922561546   34 Citations

Abstract

Chromosome 8q24 locus contains regulatory variants that modulate genetic risk to various cancers including prostate cancer (PC). However, the biological mechanism underlying this regulation is not well understood. Here, we developed a chromosome conformation capture (3C)-based multi-target sequencing technology and systematically examined three PC risk regions at the 8q24 locus and their potential regulatory targets across human genome in six cell lines. We observed frequent physical contacts of this risk locus with multiple genomic regions, in particular, inter-chromosomal interaction with CD96 at 3q13 and intra-chromosomal interaction with MYC at 8q24. We identified at least five interaction hot spots within the predicted functional regulatory elements at the 8q24 risk locus. We also found intra-chromosomal interaction genes PVT1, FAM84B and GSDMC and inter-chromosomal interaction gene CXorf36 in most of the six cell lines. Other gene regions appeared to be cell line-specific, such as RRP12 in LNCaP, USP14 in DU-145 and SMIN3 in lymphoblastoid cell line. We further found that the 8q24 functional domains more likely interacted with genomic regions containing genes enriched in critical pathways such as Wnt signaling and promoter motifs such as E2F1 and TCF3. This result suggests that the risk locus may function as a regulatory hub by physical interactions with multiple genes important for prostate carcinogenesis. Further understanding genetic effect and biological mechanism of these chromatin interactions will shed light on the newly discovered regulatory role of the risk locus in PC etiology and progression.

Author List

Du M, Yuan T, Schilter KF, Dittmar RL, Mackinnon A, Huang X, Tschannen M, Worthey E, Jacob H, Xia S, Gao J, Tillmans L, Lu Y, Liu P, Thibodeau SN, Wang L

Authors

Pengyuan Liu PhD Adjunct Professor in the Physiology department at Medical College of Wisconsin
Kala Schilter in the CTSI department at Medical College of Wisconsin - CTSI




MESH terms used to index this publication - Major topics in bold

Cell Line, Tumor
Chromatin
Chromosomes, Human, Pair 8
Genetic Association Studies
Genetic Loci
Genetic Predisposition to Disease
High-Throughput Nucleotide Sequencing
Humans
Male
Prostatic Neoplasms
Sequence Analysis, DNA
jenkins-FCD Prod-484 8aa07fc50b7f6d102f3dda2f4c7056ff84294d1d