Nucleome Analysis Reveals Structure–Function Relationships for Colon Cancer

Abstract

Chromosomal translocations and aneuploidy are hallmarks of cancer genomes; however, the impact of these aberrations on the nucleome (i.e., nuclear structure and gene expression) is not yet understood. Here, the nucleome of the colorectal cancer cell line HT-29 was analyzed using chromosome conformation capture (Hi-C) to study genome structure, complemented by RNA sequencing (RNA-seq) to determine the consequent changes in genome function. Importantly, translocations and copy number changes were identified at high resolution from Hi-C data and the structure-function relationships present in normal cells were maintained in cancer. In addition, a new copy number-based normalization method for Hi-C data was developed to analyze the effect of chromosomal aberrations on local chromatin structure. The data demonstrate that at the site of translocations, the correlation between chromatin organization and gene expression increases; thus, chromatin accessibility more directly reflects transcription. In addition, the homogeneously staining region of chromosome band 8q24 of HT-29, which includes the MYC oncogene, interacts with various loci throughout the genome and is composed of open chromatin. The methods, described herein, can be applied to the assessment of the nucleome in other cell types with chromosomal aberrations. Findings show that chromosome conformation capture identifies chromosomal abnormalities at high resolution in cancer cells and that these abnormalities alter the relationship between structure and function. .

HiGlass: Web-based Visual Exploration and Analysis of Genome Interaction Maps

“…spatial segregation of active and inactive regions of the genome, topologically associating domains (TADs), and associated peaks of contact frequency (often referred to as loops) [1,[3][4][5]. Hi-C maps have helped implicate changes in genome organization in a variety of disorders, including acute lymphoblastic leukemia [6], colorectal cancer [7], and limb development disorders [8]. More fundamentally, they provide insights into the mechanisms by which genome conformation structures arise, are maintained, and change over time [9][10][11].…”

HiPiler: Visual Exploration of Large Genome Interaction Matrices with Interactive Small Multiples

“…Biologists are interested in uncovering the mechanisms that drive global and local folding to better understand the vast and complex gene regulation network. This aids comprehension of the functional diversity of cells and how changes in the spatial conformation of the genome can cause diseases [24, 32, 40]. …”

Identification of copy number variations and translocations in cancer cells from Hi-C data

“…Recent studies have shown that rearrangements in cancer not only alter the one-dimensional (1D) but also the three-dimensional (3D) structure of the genome and individual chromosomes (Engreitz et al 2012;Ay et al 2015; Barutcu et al 2015;Harewood et al 2017;Seaman et al 2017). These studies were made possible by the development of high-throughput chromosome conformation capture techniques (e.g., Hi-C) (Lieberman-Aiden et al 2009;Rao et al 2014), which also revealed novel relationships between spatial arrangement of the genome and its function (Dixon et al 2012;Ay et al 2014;Pope et al 2014;Sexton and Cavalli 2015).…”