Chromatin interactions and candidate genes at ten prostate cancer risk loci

Abstract

Genome-wide association studies have identified more than 100 common single nucleotide polymorphisms (SNPs) that are associated with prostate cancer risk. However, the vast majority of these SNPs lie in noncoding regions of the genome. To test whether these risk SNPs regulate their target genes through long-range chromatin interactions, we applied capture-based 3C sequencing technology to investigate possible cis-interactions at ten prostate cancer risk loci in six cell lines. We identified significant physical interactions between risk regions and their potential target genes including CAPG at 2p11.2, C2orf43 at 2p24.1, RFX6 at 6q22.1, NFASC at 1q32.1, MYC at 8q24.1 and AGAP7P at 10q11.23. Most of the interaction peaks were co-localized to regions of active histone modification and transcription factor binding sites. Expression quantitative trait locus (eQTL) analysis showed suggestive eQTL signals at rs1446669, rs699664 and rs1078004 for CAPG (p < 0.004), rs13394027 for C2orf43 (p = 2.25E-27), rs10993994 and rs4631830 for AGAP7P (p < 8.02E-5). Further analysis revealed an enhancer activity at genomic region surrounding rs4631830 which was expected to disrupt HOXB-like DNA binding affinity. This study identifies a set of candidate genes and their potential regulatory variants, and provides additional evidence showing the role of long-range chromatin interactions in prostate cancer etiology.

The Genome Conformation As an Integrator of Multi-Omic Data: The Example of Damage Spreading in Cancer

“…Indeed, there are evidences that DNA topological changes occurring during the disease development support the conversion of cells to a pathological state (Jäger et al, 2015; Du et al, 2016). Considering cancer, although chromatin conformation changes are poorly understood during the tumor development, it is possible to demonstrate that oncogenic transcription-factors overexpression is associated with global, reproducible, and functionally coherent changes in the chromatin organization (Rickman et al, 2012; Taberlay et al, 2016).…”

“…However, the vast majority of these SNPs lie in noncoding regions of the genome and their interpretation is difficult (Merelli et al, 2013a; Kel et al, 2016). To test whether SNPs regulate their target genes through long-range chromatin interactions, capture-based sequencing technology have been used to investigate possible cis -interactions at different cancer risk loci (Jäger et al, 2015; Du et al, 2016), finding very interesting results in this sense. More generally, the association between chromosome conformation and epigenetic patterns is under investigation, by comparing normal and cancer tissues.…”

3C-digital PCR for quantification of chromatin interactions

“…We further tested the ligation frequency between prostate cancer risk locus 2p11.2 and gene CAPG, which was described in our previous study [12]. The anchor primer at 2q11.3 was designed at the position (chr2: 85778503) named 2L.…”

“…For the interaction between 2q11.3 and gene CAPG , primers and probe were designed as previously reported [12]. In brief, the anchor primer at 2q11.3 was designed near the cutting site chr2: 85778503 named 2L.…”

“…Here we reported a 3C-dPCR assay by incorporating dPCR technology into 3C assay [10]. We tested this assay at two prostate cancer risk regions of 8q24 and 2p11.2 for their interaction target genes MYC and CAPG [11, 12]. Our results show that 3C-dPCR is easier to use and more sensitive in determining chromatin interactions.…”