Reorganization of the 3D Genome Pinpoints Noncoding Drivers of Primary Prostate Tumors

Abstract

Prostate cancer is a heterogeneous disease whose progression is linked to genome instability. However, the impact of this instability on the noncoding genome and its three-dimensional organization to aid progression is unclear. Using primary benign and tumor tissue, we find a high concordance in higher-order three-dimensional genome organization. This concordance argues for constraints to the topology of prostate tumor genomes. Nonetheless, we identified changes in focal chromatin interactions, typical of loops bridging noncoding cis-regulatory elements, and showed how structural variants can induce these changes to guide cis-regulatory element hijacking. Such events resulted in opposing differential expression of genes found at antipodes of rearrangements. Collectively, these results argue that changes to focal chromatin interactions, as opposed to higher-order genome organization, allow for aberrant gene regulation and are repeatedly mediated by structural variants in primary prostate cancer. Significance: This work showcases how the noncoding genome can be hijacked by focal insults to its three-dimensional organization that contribute to prostate cancer oncogenesis.

Unravelling the tumour genome: The evolutionary and clinical impacts of structural variants in tumourigenesis

“…This phenomenon has been termed 'enhancer hijacking' (Figure 2C). Further, SVs can disrupt the function of oncogenes and tumour suppressor genes via alteration of higher-order chromatin structure [141][142][143] (Figure 2D). A recent study by the PCAWG demonstrated that SVs affect topologically associating domain (TAD) boundaries in a cancer-specific manner (according to overall SV burden), are able to generate new TAD structures, and can lead to marked changes in chromatin folding [142].…”

Epigenetic Modifications in Prostate Cancer Metastasis and Microenvironment

“…There is controversy over the status of the higher-order chromatin organizations in prostate cancer. It has been suggested that the higher-order chromatin organization status in prostate cancer is stable relative to benign tissues, and the changes in local chromatin interactions mediate the development of prostate cancer [ 12 ]. Conversely, other studies suggest that the higher-order chromatin organization is disordered and co-exists with the change of epigenetic in prostate cancer [ 39 ], among which the factor CAF-1, which is involved in the conformation of the higher-order chromatin organization, is thought to be significantly associated with adverse biological behavior in prostate cancer [ 40 ].…”

“…In particular, GSTP1 shows promoter hypermethylation in approximately 90% of PCa and 70% of prostatic intraepithelial neoplasia (PIN) patients [ 9 ]. In addition to DNA methylation, chromosome-related regulatory means such as histone modification [ 10 ], nucleosome localization [ 11 ], and higher-order chromatin organization [ 12 ] play important roles in the phenotypic transformation of prostate cancer. Recently, due to the breakthrough of high-throughput sequencing technology, the research for detecting RNA modifications has exploded [ 13 ].…”

Androgen Receptor-Mediated Transcription in Prostate Cancer

“…Using “normal” prostate epithelial cells and models of PCa (LNCaP and PC3), those so-called “normal” TADs were much larger, higher in number, and located in distinct positions [ 180 ]. However, low-input HiC from both primary PCa ( n = 12) and benign prostate tissues ( n = 5) demonstrated that, unlike cell lines, there was no significant difference in the number of TADs called or in TAD borders between samples [ 181 ]. Combining these data with whole-genome sequencing, they found only one structural variant (out of 260) with altered gene expression in an intra-TAD region.…”