Tales from topographic oceans: topologically associated domains and cancer

Abstract

The 3D organization of the genome within the cell nucleus has come into sharp focus over the last decade. This has largely arisen because of the application of genomic approaches that have revealed numerous levels of genomic and chromatin interactions, including topologically associated domains (TADs). The current review examines how these domains were identified, are organized, how their boundaries arise and are regulated, and how genes within TADs are coordinately regulated. There are many examples of the disruption to TAD structure in cancer and the altered regulation, structure and function of TADs are discussed in the context of hormone responsive cancers, including breast, prostate and ovarian cancer. Finally, some aspects of the statistical insight and computational skills required to interrogate TAD organization are considered and future directions discussed.

Keywords: CTCF; breast cancer; cohesin; enhancer; ovarian cancer; prostate cancer; topologically associated domain.

Figure 1:. TAD organization in health and disease.

A. In normal cells TADs are organized such that boundaries arise by the action of multi-protein complexes centered on CTCF and cohesin complexes. These act to insulate the contents of the TAD which range in size from 100 kb to 1–2 mb. Within a TAD, enhancers (in orange) regulate target genes through further looping events and exert positive and negative impacts on gene expression. Often these gene expression patterns are highly coordinated and governed by multiple enhancer interactions. B. In cancer cells there many examples of these process being corrupted. There is good evidence that boundary function is altered (1) with loss and gain of boundaries and changing the TAD structure. Generally, it appears the cancer genome gains more TADs of shorter length. This change of TAD structure can change enhancer function (2, 3) such that previously insulated genes are subsequently regulated by new enhancers. This is further distorted by structural variations impacting boundary function (1) and enhancer responses (2,3). The coordinated gene regulation within a TAD also allows for emergent changes in epigenetic regulation (4). That is, mutations in epigenetic regulators such as EZH2 can modestly change the regulation of individual genes in a TAD, but the collective effect on all genes is pronounced if all the genes are on a pathway for example.

Figure 2:. Mutation, copy number variation and expression of genes involved in boundary formation in hormone responsive cancers.

Gene mutation, copy number variation and expression z-score pan-cancer data for breast (BRCA), ovarian (OV), pancreatic (PAAD), prostate (PRAD), thyroid (TH), pheochromocytoma (PCPG), Testicular Germ Cell (TCG), Adrenocortical (ACC) were downloaded using the R platform for statistical computing using the cgdsr package. The genes selected were chosen by the studies highlighted in the text, as well as choosing paralogs identified by Human Genome Nomenclature. Gene mutation and copy number variation data was normalized to the number of tumors within the cohort, and also normalized to gene length for the mutation data. The normalized mutation, copy number variation and expression was then visualized as a heatmap (pheatmap) using average Manhattan clustering.