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Prostate cancer risk locus at 8q24 as a regulatory hub by physical interactions with multiple genomic loci across the genome

2014-08-22 00:02:15

Human Molecular Genetics; 22 AUG 2014; DOI: 10.1093/hmg/ddu426



Meijun Du, Tiezheng Yuan, Kala F. Schilter, Rachel L. Dittmar, Alexander Mackinnon, Xiaoyi Huang, Michael Tschannen, Elizabeth Worthey, Howard Jacob, Shu Xia, Jianzhong Gao, Lori Tillmans, Yan Lu, Pengyuan Liu, Stephen N. Thibodeau, Liang Wang



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 multiple target sequencing (3C-MTS) 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 LCL. 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.



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