title: Three-dimensional disorganization of the cancer genome occurs coincident with long-range genetic and epigenetic alterations.
abstract: A three-dimensional chromatin state underpins the structural and functional basis of the genome by bringing regulatory elements and genes into close spatial proximity to ensure proper, cell-type-specific gene expression profiles. Here, we performed Hi-C chromosome conformation capture sequencing to investigate how three-dimensional chromatin organization is disrupted in the context of copy-number variation, long-range epigenetic remodeling, and atypical gene expression programs in prostate cancer. We find that cancer cells retain the ability to segment their genomes into megabase-sized topologically associated domains (TADs); however, these domains are generally smaller due to establishment of additional domain boundaries. Interestingly, a large proportion of the new cancer-specific domain boundaries occur at regions that display copy-number variation. Notably, a common deletion on 17p13.1 in prostate cancer spanning the TP53 tumor suppressor locus results in bifurcation of a single TAD into two distinct smaller TADs. Change in domain structure is also accompanied by novel cancer-specific chromatin interactions within the TADs that are enriched at regulatory elements such as enhancers, promoters, and insulators, and associated with alterations in gene expression. We also show that differential chromatin interactions across regulatory regions occur within long-range epigenetically activated or silenced regions of concordant gene activation or repression in prostate cancer. Finally, we present a novel visualization tool that enables integrated exploration of Hi-C interaction data, the transcriptome, and epigenome. This study provides new insights into the relationship between long-range epigenetic and genomic dysregulation and changes in higher-order chromatin interactions in cancer.
authors.affiliation: Epigenetics Research Laboratory, Genomics and Epigenetics Division, Garvan Institute of Medical Research, Darlinghurst, New South Wales 2010, Australia; St. Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Darlinghurst, New South Wales 2010, Australia;
authors.forename: Phillippa C
authors.initials: PC
authors.lastname: Taberlay
authors.affiliation: Epigenetics Research Laboratory, Genomics and Epigenetics Division, Garvan Institute of Medical Research, Darlinghurst, New South Wales 2010, Australia; St. Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Darlinghurst, New South Wales 2010, Australia;
authors.forename: Joanna
authors.initials: J
authors.lastname: Achinger-Kawecka
authors.affiliation: Bioinformatics Division, Walter and Eliza Hall Institute, Parkville, Victoria 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, Victoria 3010, Australia;
authors.forename: Aaron T L
authors.initials: AT
authors.lastname: Lun
authors.affiliation: Epigenetics Research Laboratory, Genomics and Epigenetics Division, Garvan Institute of Medical Research, Darlinghurst, New South Wales 2010, Australia;
authors.forename: Fabian A
authors.initials: FA
authors.lastname: Buske
authors.affiliation: Epigenetics Research Laboratory, Genomics and Epigenetics Division, Garvan Institute of Medical Research, Darlinghurst, New South Wales 2010, Australia;
authors.forename: Kenneth
authors.initials: K
authors.lastname: Sabir
authors.affiliation: Epigenetics Research Laboratory, Genomics and Epigenetics Division, Garvan Institute of Medical Research, Darlinghurst, New South Wales 2010, Australia;
authors.forename: Cathryn M
authors.initials: CM
authors.lastname: Gould
authors.affiliation: Epigenetics Research Laboratory, Genomics and Epigenetics Division, Garvan Institute of Medical Research, Darlinghurst, New South Wales 2010, Australia; St. Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Darlinghurst, New South Wales 2010, Australia;
authors.forename: Elena
authors.initials: E
authors.lastname: Zotenko
authors.affiliation: Epigenetics Research Laboratory, Genomics and Epigenetics Division, Garvan Institute of Medical Research, Darlinghurst, New South Wales 2010, Australia;
authors.forename: Saul A
authors.initials: SA
authors.lastname: Bert
authors.affiliation: Epigenetics Research Laboratory, Genomics and Epigenetics Division, Garvan Institute of Medical Research, Darlinghurst, New South Wales 2010, Australia;
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Giles
authors.affiliation: CSIRO, North Ryde, New South Wales 2113, Australia;
authors.forename: Denis C
authors.initials: DC
authors.lastname: Bauer
authors.affiliation: Bioinformatics Division, Walter and Eliza Hall Institute, Parkville, Victoria 3052, Australia; Department of Mathematics and Statistics, University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Gordon K
authors.initials: GK
authors.lastname: Smyth
authors.affiliation: Epigenetics Research Laboratory, Genomics and Epigenetics Division, Garvan Institute of Medical Research, Darlinghurst, New South Wales 2010, Australia; St. Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Darlinghurst, New South Wales 2010, Australia;
authors.forename: Clare
authors.initials: C
authors.lastname: Stirzaker
authors.affiliation: Epigenetics Research Laboratory, Genomics and Epigenetics Division, Garvan Institute of Medical Research, Darlinghurst, New South Wales 2010, Australia; CSIRO, North Ryde, New South Wales 2113, Australia;
authors.forename: Sean I
authors.initials: SI
authors.lastname: O'Donoghue
authors.affiliation: Epigenetics Research Laboratory, Genomics and Epigenetics Division, Garvan Institute of Medical Research, Darlinghurst, New South Wales 2010, Australia; St. Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Darlinghurst, New South Wales 2010, Australia;
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Clark
mesh_terms: D000076246:CCCTC-Binding Factor; D045744:Cell Line, Tumor; D002843:Chromatin / Q000235:genetics*; D004742:Enhancer Elements, Genetic; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D015894:Genome, Human; D006657:Histones / Q000378:metabolism; D006801:Humans; D058977:Molecular Sequence Annotation; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D012097:Repressor Proteins / Q000502:physiology
chemical_list: D000076246:CCCTC-Binding Factor; C000619697:CTCF protein, human; D002843:Chromatin; D006657:Histones; D012097:Repressor Proteins