Alterations in Three-Dimensional Organization of the Cancer Genome and Epigenome.

Joanna Achinger-Kawecka,Susan J Clark,Phillippa C Taberlay

doi:10.1101/sqb.2016.81.031013

Abstract

The structural and functional basis of the genome is provided by the three-dimensional (3D) chromatin state. To enable accurate gene regulation, enhancer elements and promoter regions are brought into close spatial proximity to ensure proper, cell type-specific gene expression. In cancer, genetic and epigenetic processes can deregulate the transcriptional program. To investigate whether the 3D chromatin state is also disrupted in cancer we performed Hi-C chromosome conformation sequencing in normal and prostate cancer cells and compared the chromatin interaction maps with changes to the genome and epigenome. Notably, we find that additional topologically associated domain (TAD) boundaries are formed in cancer cells resulting in smaller TADs and altered gene expression profiles. The new TAD boundaries are commonly associated with copy-number changes observed in the cancer genome. We also identified new cancer-specific chromatin loops within TADs that are enriched for enhancers and promoters. Finally, we find that many of the long-range epigenetically silenced (LRES) and long-range epigenetically active (LREA) regions in cancer are characterized by differential chromatin interactions. Together our data provide a new insight into charting alterations in higher-order structure and the relationship with genetic, epigenetic, and transcriptional changes across the cancer genome.

Highlights

A 400- to 600-kb cancer-specific deletion on Chromosome 17p13.1 is associated with the establishment of a new domain boundary in both prostate cancer cell lines and a resulting change in local interactions across this region (Fig. 3)
The findings show that the segmentation of the genome into well-defined topologically associated domain (TAD) is still maintained in the cancer genome, the characteristics of TADs in cancer cells are significantly different to TADs in normal cells
We found that TAD boundaries in all three cell types were highly enriched for CCCTC-binding factor (CTCF) (Fig. 2D), with 7% of all CTCF binding sites being located at TAD boundaries

Summary

Introduction

A 400- to 600-kb cancer-specific deletion on Chromosome 17p13.1 is associated with the establishment of a new domain boundary in both prostate cancer cell lines and a resulting change in local interactions across this region (Fig. 3). Consistent with this finding, previous reports suggested that genomic deletions at TAD borders in normal cells result in a change in local chromatin organization and in a formation of new domain boundaries (Nora et al 2012; Ibn-Salem et al 2014).

Results

Conclusion