Oncogene-mediated alterations in chromatin conformation

Abstract

Emerging evidence suggests that chromatin adopts a nonrandom 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 interchromosome interactions upon overexpression of ERG, an oncogenic transcription factor frequently overexpressed 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 overexpression 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, and PML-RARα.M ounting evidence suggests that many genes dynamically colocalize to shared nuclear compartments that favor gene activation or silencing (1-3). As demonstrated by chromosome conformation capture (3C) (4), ligand-bound androgen receptors (AR) and estrogen receptors mediate looped chromatin structures resulting in coordinated transcription of target genes (5, 6). In embryonic carcinoma cells, the PolyComb complex subunit EZH2 represses some of its target genes via the formation of similar looped chromatin structures (7). Trans-interactions that regulate gene expression have also been reported (8-10). These data suggest that oncogenic transcriptional regulators are capable of inducing changes in chromatin structures. These studies have mainly focused on local chromatin structures, and it is still unclear whether more global changes occur in the process of oncogene-mediated transformation. A broader implication of these observations is that global chromatin organization changes could impact functional and phenotypic aspects of cancer.To globally investigate oncogene-mediated chromatin structure changes we focused on ERG, the ETS-family transcription factor most frequently rearranged and overexpressed in prostate cancer through the TMPRSS2-ERG and other gene fusions involving androgen-responsive promoters (11-13). ERG interacts with several cofactors (14) and other transcription factors including AR to regulate the expression of thousands of genes that favor dedifferentiation, cell invasion, and neoplastic transformation of prostate epithelium when overexpressed (15-20). We therefore hypothesized that changes in global gene expression induced by ERG overexpression could be associated with global changes in the 3D structure of chromosomes.Results ERG Overexpression Is Associated with Chromatin Topology. To test our hypothesis, we used...

Altered DNA Methylation Landscapes of Polycomb-Repressed Loci Are Associated with Prostate Cancer Progression and ERG Oncogene Expression in Prostate Cancer

“…This observed relationship between ERG expression and gene specific DNA methylation is not surprising given the role of ERG as a transcription factor that likely requires epigenetic cofactors in modifying and remodeling surrounding chromatin to exert its effects. Recent functional work in ERG-overexpressing cells has identified global changes in chromatin interactions that are likely dependent on chromatin remodeling and epigenetic changes (36). Furthermore, ERG expression has been shown to correlate with HDAC1 expression and also induces EZH2 expression (37,38), both of which may cooperate with DNA methylation to promote a silent chromatin state (30,39).…”

Genome-wide map of regulatory interactions in the human genome

“…However, increasing evidence suggests that in addition to local interactions, 3D contacts between distal regulatory elements play an important role in gene regulation (Gondor and Ohlsson 2009;Schoenfelder et al 2010). Such contacts have been implicated in diverse biological phenomena including development, cancer, and immune response (Jhunjhunwala et al 2008;Kenter et al 2012;Rickman et al 2012;Apostolou et al 2013;Liu and Cheung 2013;PhillipsCremins et al 2013). However, due to the limited ability to study three-dimensional (3D) chromatin structure with sufficient breadth and resolution, our knowledge regarding the characteristics and impact of chromatin structure remains limited.…”

The Breast Cancer DNA Interactome

“…Rickman et al, for example, found that overexpression of an oncogenic transcription factor in normal cells leads to large-scale changes in chromatin organization [36]. We have seen that there is a dramatic change in long-range interactions in cancer cells compared with cells derived from normal tissues.…”