Disruption of the 3D cancer genome blueprint.

Recent advances in chromosome conformation capture technologies are improving the current appreciation of how 3D genome architecture affects its function in different cell types and disease. Long-range chromatin interactions are organized into topologically associated domains, which are known to play a role in constraining gene expression patterns. However, in cancer cells there are alterations in the 3D genome structure, which impacts on gene regulation. Disruption of topologically associated domains architecture can result in alterations in chromatin interactions that bring new regulatory elements and genes together, leading to altered expression of oncogenes and tumor suppressor genes. Here, we discuss the impact of genetic and epigenetic changes in cancer and how this affects the spatial organization of chromatin. Understanding how disruptions to the 3D architecture contribute to the cancer genome will provide novel insights into the principles of epigenetic gene regulation in cancer and mechanisms responsible for cancer associated mutations and rearrangements.

[1]  L. Ettwiller,et al.  Functional and topological characteristics of mammalian regulatory domains , 2014, Genome research.

[2]  Jing Liang,et al.  Chromatin architecture reorganization during stem cell differentiation , 2015, Nature.

[3]  Neva C. Durand,et al.  A 3D Map of the Human Genome at Kilobase Resolution Reveals Principles of Chromatin Looping , 2014, Cell.

[4]  Mark D. Robinson,et al.  Consolidation of the cancer genome into domains of repressive chromatin by long-range epigenetic silencing (LRES) reduces transcriptional plasticity , 2010, Nature Cell Biology.

[5]  Neva C. Durand,et al.  Chromatin extrusion explains key features of loop and domain formation in wild-type and engineered genomes , 2015, Proceedings of the National Academy of Sciences.

[6]  R. Houlston,et al.  Capture Hi-C identifies the chromatin interactome of colorectal cancer risk loci , 2015, Nature Communications.

[7]  Jill M Dowen,et al.  Control of Cell Identity Genes Occurs in Insulated Neighborhoods in Mammalian Chromosomes , 2014, Cell.

[8]  Pedro P. Rocha,et al.  CTCF establishes discrete functional chromatin domains at the Hox clusters during differentiation , 2015, Science.

[9]  Peter H. L. Krijger,et al.  CTCF Binding Polarity Determines Chromatin Looping. , 2015, Molecular cell.

[10]  Wolfgang Huber,et al.  A Discrete Transition Zone Organizes the Topological and Regulatory Autonomy of the Adjacent Tfap2c and Bmp7 Genes , 2015, PLoS genetics.

[11]  S. Clark,et al.  Epigenetic inactivation of a cluster of genes flanking MLH1 in microsatellite-unstable colorectal cancer. , 2007, Cancer research.

[12]  C. Nusbaum,et al.  Chromosome Conformation Capture Carbon Copy (5C): a massively parallel solution for mapping interactions between genomic elements. , 2006, Genome research.

[13]  John A. Stamatoyannopoulos,et al.  Cell-type-specific long-range looping interactions identify distant regulatory elements of the CFTR gene , 2010, Nucleic acids research.

[14]  S. Gabriel,et al.  Discovery and saturation analysis of cancer genes across 21 tumor types , 2014, Nature.

[15]  Michael S. Becker,et al.  Spatial Organization of the Mouse Genome and Its Role in Recurrent Chromosomal Translocations , 2012, Cell.

[16]  Matthew T. Maurano,et al.  Role of DNA Methylation in Modulating Transcription Factor Occupancy. , 2015, Cell reports.

[17]  Shawn M. Gillespie,et al.  Insulator dysfunction and oncogene activation in IDH mutant gliomas , 2015, Nature.

[18]  Kathy Pritchard-Jones,et al.  Frequent Long-Range Epigenetic Silencing of Protocadherin Gene Clusters on Chromosome 5q31 in Wilms' Tumor , 2009, PLoS genetics.

[19]  Michael Q. Zhang,et al.  CRISPR Inversion of CTCF Sites Alters Genome Topology and Enhancer/Promoter Function , 2015, Cell.

[20]  Clare Stirzaker,et al.  Epigenetic remodeling in colorectal cancer results in coordinate gene suppression across an entire chromosome band , 2006, Nature Genetics.

[21]  A. Visel,et al.  Disruptions of Topological Chromatin Domains Cause Pathogenic Rewiring of Gene-Enhancer Interactions , 2015, Cell.

[22]  Jesse R. Dixon,et al.  Topological Domains in Mammalian Genomes Identified by Analysis of Chromatin Interactions , 2012, Nature.

[23]  Thomas G. Gilgenast,et al.  Local Genome Topology Can Exhibit an Incompletely Rewired 3D-Folding State during Somatic Cell Reprogramming. , 2016, Cell stem cell.

[24]  E. Liu,et al.  An Oestrogen Receptor α-bound Human Chromatin Interactome , 2009, Nature.

[25]  Aaron T. L. Lun,et al.  Three-dimensional disorganization of the cancer genome occurs coincident with long-range genetic and epigenetic alterations , 2016, Genome research.

[26]  Leping Li,et al.  Characterization of constitutive CTCF/cohesin loci: a possible role in establishing topological domains in mammalian genomes , 2013, BMC Genomics.

[27]  K. Sandhu,et al.  Circular chromosome conformation capture (4C) uncovers extensive networks of epigenetically regulated intra- and interchromosomal interactions , 2006, Nature Genetics.

[28]  Mathieu Blanchette,et al.  Classifying leukemia types with chromatin conformation data , 2014, Genome Biology.

[29]  G. Stein,et al.  Chromatin interaction analysis reveals changes in small chromosome and telomere clustering between epithelial and breast cancer cells , 2015, Genome Biology.

[30]  J. Dekker,et al.  Capturing Chromosome Conformation , 2002, Science.

[31]  L. Horvath,et al.  DLEC1 and MLH1 promoter methylation are associated with poor prognosis in non-small cell lung carcinoma , 2008, British Journal of Cancer.

[32]  Christopher A. Haiman,et al.  The 8q24 cancer risk variant rs6983267 demonstrates long-range interaction with MYC in colorectal cancer , 2009, Nature Genetics.

[33]  S. Thibodeau,et al.  Chromatin interactions and candidate genes at ten prostate cancer risk loci , 2016, Scientific Reports.

[34]  L. Mirny,et al.  The 3D Genome as Moderator of Chromosomal Communication , 2016, Cell.

[35]  B. Steensel,et al.  Nuclear organization of active and inactive chromatin domains uncovered by chromosome conformation capture–on-chip (4C) , 2006, Nature Genetics.

[36]  V. Corces,et al.  CTCF: an architectural protein bridging genome topology and function , 2014, Nature Reviews Genetics.

[37]  Hongling Liao,et al.  Long-range enhancers on 8q24 regulate c-Myc , 2010, Proceedings of the National Academy of Sciences.

[38]  I. Amit,et al.  Comprehensive mapping of long range interactions reveals folding principles of the human genome , 2011 .

[39]  Niko Välimäki,et al.  CTCF/cohesin-binding sites are frequently mutated in cancer , 2015, Nature Genetics.

[40]  Peter H. L. Krijger,et al.  Cell-of-Origin-Specific 3D Genome Structure Acquired during Somatic Cell Reprogramming , 2016, Cell stem cell.

[41]  W. Bickmore,et al.  Estrogen-induced chromatin decondensation and nuclear re-organization linked to regional epigenetic regulation in breast cancer , 2015, Genome Biology.

[42]  P. Neiman,et al.  An exceptionally conserved transcriptional repressor, CTCF, employs different combinations of zinc fingers to bind diverged promoter sequences of avian and mammalian c-myc oncogenes , 1996, Molecular and cellular biology.

[43]  G. Morgan,et al.  Translocations at 8q24 juxtapose MYC with genes that harbor superenhancers resulting in overexpression and poor prognosis in myeloma patients , 2014, Blood Cancer Journal.

[44]  J. Sedat,et al.  Spatial partitioning of the regulatory landscape of the X-inactivation centre , 2012, Nature.

[45]  Martin S. Taylor,et al.  Mutational Biases Drive Elevated Rates of Substitution at Regulatory Sites across Cancer Types , 2016, PLoS genetics.

[46]  D. Pinkel,et al.  Regional copy number–independent deregulation of transcription in cancer , 2006, Nature Genetics.

[47]  M. Rubin,et al.  Oncogene-mediated alterations in chromatin conformation , 2012, Proceedings of the National Academy of Sciences.

[48]  J. Dekker,et al.  The long-range interaction landscape of gene promoters , 2012, Nature.

[49]  G. Coetzee,et al.  8q24 prostate, breast, and colon cancer risk loci show tissue-specific long-range interaction with MYC , 2010, Proceedings of the National Academy of Sciences.

[50]  Dario Strbenac,et al.  Regional activation of the cancer genome by long-range epigenetic remodeling. , 2013, Cancer cell.

[51]  Taylor Jensen,et al.  Agglomerative epigenetic aberrations are a common event in human breast cancer. , 2008, Cancer research.

[52]  Michael D. Cole,et al.  Upregulation of c-MYC in cis through a Large Chromatin Loop Linked to a Cancer Risk-Associated Single-Nucleotide Polymorphism in Colorectal Cancer Cells , 2010, Molecular and Cellular Biology.

[53]  M. Spielmann,et al.  A large genomic deletion leads to enhancer adoption by the lamin B1 gene: a second path to autosomal dominant adult-onset demyelinating leukodystrophy (ADLD) , 2015, Human molecular genetics.

[54]  Jennifer E. Phillips-Cremins,et al.  Architectural Protein Subclasses Shape 3D Organization of Genomes during Lineage Commitment , 2013, Cell.

[55]  Wouter de Laat,et al.  CTCF mediates long-range chromatin looping and local histone modification in the beta-globin locus. , 2006, Genes & development.

[56]  A. Ashworth,et al.  Unbiased analysis of potential targets of breast cancer susceptibility loci by Capture Hi-C , 2014, Genome research.

[57]  Job Dekker,et al.  Invariant TAD Boundaries Constrain Cell-Type-Specific Looping Interactions between Promoters and Distal Elements around the CFTR Locus. , 2016, American journal of human genetics.

[58]  Matthew T. Maurano,et al.  Widespread plasticity in CTCF occupancy linked to DNA methylation , 2012, Genome research.

[59]  S. Mundlos,et al.  Formation of new chromatin domains determines pathogenicity of genomic duplications , 2016, Nature.

[60]  Daniel S. Day,et al.  Activation of proto-oncogenes by disruption of chromosome neighborhoods , 2015, Science.

[61]  Britta A. M. Bouwman,et al.  A Single Oncogenic Enhancer Rearrangement Causes Concomitant EVI1 and GATA2 Deregulation in Leukemia , 2014, Cell.

[62]  V. Corces,et al.  A CTCF Code for 3D Genome Architecture , 2015, Cell.

[63]  V. Corces,et al.  CTCF: Master Weaver of the Genome , 2009, Cell.