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
08/26/2014Pubmed ID
25149474Pubmed Central ID
PMC4262497DOI
10.1093/hmg/ddu426Scopus ID
2-s2.0-84922561546 (requires institutional sign-in at Scopus site) 47 CitationsAbstract
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 LAuthor
Kala Schilter in the CTSI department at Medical College of Wisconsin - CTSIMESH terms used to index this publication - Major topics in bold
Cell Line, TumorChromatin
Chromosomes, Human, Pair 8
Genetic Association Studies
Genetic Loci
Genetic Predisposition to Disease
High-Throughput Nucleotide Sequencing
Humans
Male
Prostatic Neoplasms
Sequence Analysis, DNA
