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

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.

Type Conference proceedings
ISBN 1943-4456 (Electronic) 0091-7451 (Linking)
Authors Achinger-Kawecka, J.; Taberlay, P. C.; Clark, S. J.
Responsible Garvan Author Prof Susan Clark
Publisher Name Cold Spring Harb Symp Quant Biol
Published Date 2017-01-31 00:00:00
Published Volume 81
Published Pages 41-51
Status Published in-print
DOI 10.1101/sqb.2016.81.031013
URL link to publisher's version https://www.ncbi.nlm.nih.gov/pubmed/28424341
OpenAccess link to author's accepted manuscript version https://publications.gimr.garvan.org.au/open-access/14134