title: 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.Implications: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.Mol Cancer Res; 15(7); 821-30. ©2017 AACR.
authors.affiliation: Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan.
authors.forename: Laura
authors.initials: L
authors.lastname: Seaman
authors.affiliation: Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan.
authors.forename: Haiming
authors.initials: H
authors.lastname: Chen
authors.affiliation: Cancer Genomics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Markus
authors.initials: M
authors.lastname: Brown
authors.affiliation: Cancer Genomics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Darawalee
authors.initials: D
authors.lastname: Wangsa
authors.affiliation: Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan.
authors.forename: Geoff
authors.initials: G
authors.lastname: Patterson
authors.affiliation: Gastrointestinal and Pancreatic Oncology Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Catalonia, Spain.|Unitat de Biologia Cellular i Genètica Mèdica, Departament de Biologia Cellular, Fisiologia i Immunologia, Facultat de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Catalonia, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Camps
authors.affiliation: Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan.|Departments of Internal Medicine and Human Genetics, School of Public Health, University of Michigan, Ann Arbor, Michigan.
authors.forename: Gilbert S
authors.initials: GS
authors.lastname: Omenn
authors.affiliation: Cancer Genomics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Ried
authors.affiliation: Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan. indikar@umich.edu.|Department of Mathematics, University of Michigan, Ann Arbor, Michigan.
authors.forename: Indika
authors.initials: I
authors.lastname: Rajapakse
mesh_terms: D002467:Cell Nucleus / Q000235:genetics*; D002875:Chromosomes / Q000648:ultrastructure*; D003110:Colonic Neoplasms / Q000235:genetics* / Q000473:pathology; D019295:Computational Biology; D056915:DNA Copy Number Variations / Q000235:genetics; D015894:Genome, Human / Q000235:genetics; D056914:Genomic Structural Variation / Q000235:genetics*; D019073:HT29 Cells; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D009690:Nucleic Acid Conformation; D013329:Structure-Activity Relationship; D014178:Translocation, Genetic / Q000235:genetics