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Primary prostate Hi-C

ABSTRACT: Prostate cancer is a heterogeneous disease whose progression is linked to genome instability. Despite large-scale tumour sequencing efforts, the impact of mutations on the genetic architecture in cancer remains ill-defined due to limited integration of genomics data across dimensions. We addressed this limitation by assessing the impact of structural variants on the chromatin states and the three-dimensional organization across benign and malignant primary prostate genomes. We find high concordance in the three-dimensional genome organization between malignant and benign prostate tissues, arguing for constraints to the three-dimensional genome of prostate tumours. Moreover, we identify structural variants as effectors of changes to focal chromatin interactions, guiding cis-regulatory element hijacking that imposes opposing expression changes on genes found at antipodes of a rearrangement. This leads to the repression of tumour suppressor gene expression and up-regulation of oncogenes, such as at the TMPRSS2-ERG and PMEPA1-ZNF156 loci. Collectively, our results argue that cis-regulatory element hijacking by structural variants overshadows large-scale topological changes to alter gene regulation and promote oncogenesis.

PROVIDER: EGAS00001005014 | EGA |

REPOSITORIES: EGA

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Project description:Emerging evidence suggests that chromatin adopts a non-random three-dimensional (3D) topology and that the organization of genes into structural hubs and domains affects their transcriptional status. How chromatin conformation changes in diseases such as cancer is poorly understood. Moreover, how oncogenic transcription factors, which bind to thousands of sites across the genome, influence gene regulation by globally altering the topology of chromatin requires further investigation. To address these questions, we performed unbiased high-resolution mapping of intra- and inter-chromosome interactions upon over-expression of ERG, an oncogenic transcription factor frequently over-expressed in prostate cancer as a result of a gene fusion. By integrating data from genome-wide chromosome conformation capture (Hi-C), ERG binding and gene expression, we demonstrate that oncogenic transcription factor over-expression is associated with global, reproducible and functionally coherent changes in chromatin organization. The results presented here have broader implications, as genomic alterations in other cancer types frequently give rise to aberrant transcription factor expression e.g., EWS-FLI1, c-Myc, n-Myc, PML-RARα. We used stable isogenic, normal benign prostate epithelial cell lines (RWPE1) that differ with respect to ERG3 over-expression. To test whether ERG over-expression is associated with global changes in chromatin structure, we performed unbiased chromatin interaction mapping using the Hi-C technique from both RWPE1-ERG and RWPE1-GFP cells, with biological replicates. Successful fill-in and ligation were determined as previously reported by testing for a known interaction between two distant genomic loci located on chromosome 6. The Hi-C libraries were paired-end sequenced using an Illumina GAIIx platform. Following alignment to the human genome (hg18) and filtering to remove un-ligated and self-ligated DNA, we identified intra-chromosomal (or cis-) and inter-chromosomal (or trans-) interactions in both RWPE1 cell lines. To characterize ERG binding and ERG-mediated gene expression changes in these cells, we performed chromatin-immunoprecipitation combined with high-throughput sequencing (ChIP-seq) and RNA sequencing (RNA-seq). ERG was bound to 6,398 sites in RPWE1-ERG cells. Based on paired-end RNA-seq data from both cell lines, 1,266 genes were differentially expressed between RWPE1-ERG and RWPE1-GFP cell lines.

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Primary prostate Hi-C

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