The effect of translocation-induced nuclear reorganization on gene expression.

Translocations are known to affect the expression of genes at the breakpoints and, in the case of unbalanced translocations, alter the gene copy number. However, a comprehensive understanding of the functional impact of this class of variation is lacking. Here, we have studied the effect of balanced chromosomal rearrangements on gene expression by comparing the transcriptomes of cell lines from controls and individuals with the t(11;22)(q23;q11) translocation. The number of differentially expressed transcripts between translocation-carrying and control cohorts is significantly higher than that observed between control samples alone, suggesting that balanced rearrangements have a greater effect on gene expression than normal variation. Many of the affected genes are located along the length of the derived chromosome 11. We show that this chromosome is concomitantly altered in its spatial organization, occupying a more central position in the nucleus than its nonrearranged counterpart. Derivative 22-mapping chromosome 22 genes, on the other hand, remain in their usual environment. Our results are consistent with recent studies that experimentally altered nuclear organization, and indicated that nuclear position plays a functional role in regulating the expression of some genes in mammalian cells. Our study suggests that chromosomal translocations can result in hitherto unforeseen, large-scale changes in gene expression that are the consequence of alterations in normal chromosome territory positioning. This has consequences for the patterns of gene expression change seen during tumorigenesis-associated genome instability and during the karyotype changes that lead to speciation.

[1]  Tomas W. Fitzgerald,et al.  Origins and functional impact of copy number variation in the human genome , 2010, Nature.

[2]  B. Emanuel,et al.  Risk of breast cancer not increased in translocation 11;22 carriers: Analysis of 80 pedigrees , 2010, American journal of medical genetics. Part A.

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

[4]  M. Hurles,et al.  Copy number variation in human health, disease, and evolution. , 2009, Annual review of genomics and human genetics.

[5]  Helen A. Foster,et al.  The spatial repositioning of adipogenesis genes is correlated with their expression status in a porcine mesenchymal stem cell adipogenesis model system , 2009, Chromosoma.

[6]  Wendy A. Bickmore,et al.  Transcription factories: gene expression in unions? , 2009, Nature Reviews Genetics.

[7]  D. Kleinjan,et al.  Cis-ruption mechanisms: disruption of cis-regulatory control as a cause of human genetic disease. , 2009, Briefings in functional genomics & proteomics.

[8]  W. Bickmore,et al.  Transcription and the nuclear periphery: edge of darkness? , 2009, Current opinion in genetics & development.

[9]  A. Reymond,et al.  Copy number variants, diseases and gene expression. , 2009, Human molecular genetics.

[10]  Charlotte N. Henrichsen,et al.  Segmental copy number variation shapes tissue transcriptomes , 2009, Nature Genetics.

[11]  P. Cahan,et al.  The impact of copy number variation on local gene expression in mouse hematopoietic stem/progenitor cells , 2009, Nature Genetics.

[12]  Iuliana Ionita-Laza,et al.  Genetic association analysis of copy-number variation (CNV) in human disease pathogenesis. , 2009, Genomics.

[13]  Dirk Schübeler,et al.  Global Reorganization of Replication Domains During Embryonic Stem Cell Differentiation , 2008, PLoS biology.

[14]  F. Iborra,et al.  Association between active genes occurs at nuclear speckles and is modulated by chromatin environment , 2008, The Journal of cell biology.

[15]  Alexandre Reymond,et al.  Abnormal social behaviors and altered gene expression rates in a mouse model for Potocki-Lupski syndrome. , 2008, Human molecular genetics.

[16]  Joshua M. Korn,et al.  Mapping and sequencing of structural variation from eight human genomes , 2008, Nature.

[17]  S. V. Heesch,et al.  Distribution and functional impact of DNA copy number variation in the rat , 2008, Nature Genetics.

[18]  Concetta Federico,et al.  The radial arrangement of the human chromosome 7 in the lymphocyte cell nucleus is associated with chromosomal band gene density , 2008, Chromosoma.

[19]  E. Bertolino,et al.  Transcriptional repression mediated by repositioning of genes to the nuclear lamina , 2008, Nature.

[20]  Elizabeth Kerr,et al.  Recruitment to the Nuclear Periphery Can Alter Expression of Genes in Human Cells , 2008, PLoS genetics.

[21]  Prabhakar R. Gudla,et al.  Allele-specific nuclear positioning of the monoallelically expressed astrocyte marker GFAP. , 2008, Genes & development.

[22]  Jennifer A. Mitchell,et al.  Transcription factories are nuclear subcompartments that remain in the absence of transcription. , 2008, Genes & development.

[23]  B. Emanuel,et al.  From microscopes to microarrays: dissecting recurrent chromosomal rearrangements , 2007, Nature Reviews Genetics.

[24]  Philip M. Kim,et al.  Paired-End Mapping Reveals Extensive Structural Variation in the Human Genome , 2007, Science.

[25]  D. Koller,et al.  Population genomics of human gene expression , 2007, Nature Genetics.

[26]  Charlotte N. Henrichsen,et al.  Side effects of genome structural changes. , 2007, Current opinion in genetics & development.

[27]  Cameron S. Osborne,et al.  Myc Dynamically and Preferentially Relocates to a Transcription Factory Occupied by Igh , 2007, PLoS biology.

[28]  E. Heard,et al.  The ins and outs of gene regulation and chromosome territory organisation. , 2007, Current opinion in cell biology.

[29]  P. Fraser,et al.  Nuclear organization of the genome and the potential for gene regulation , 2007, Nature.

[30]  R. Redon,et al.  Relative Impact of Nucleotide and Copy Number Variation on Gene Expression Phenotypes , 2007, Science.

[31]  Tom Misteli,et al.  Cell biology: Chromosome territories , 2007, Nature.

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

[33]  D. Conrad,et al.  Global variation in copy number in the human genome , 2006, Nature.

[34]  M. Noor,et al.  Speciation genetics: evolving approaches , 2006, Nature Reviews Genetics.

[35]  A. Röpke,et al.  High incidence of familial breast cancer segregates with constitutional t(11;22)(q23;q11) , 2006, Genes, chromosomes & cancer.

[36]  M. Kozubek,et al.  Localization of genetic elements of intact and derivative chromosome 11 and 22 territories in nuclei of Ewing sarcoma cells. , 2006, Journal of structural biology.

[37]  Charlotte N. Henrichsen,et al.  Submicroscopic deletion in patients with Williams-Beuren syndrome influences expression levels of the nonhemizygous flanking genes. , 2006, American journal of human genetics.

[38]  Thomas Cremer,et al.  Chromosome territories--a functional nuclear landscape. , 2006, Current opinion in cell biology.

[39]  T. Misteli,et al.  Neural induction promotes large-scale chromatin reorganisation of the Mash1 locus , 2006, Journal of Cell Science.

[40]  Roland Eils,et al.  Local gene density predicts the spatial position of genetic loci in the interphase nucleus. , 2005, Experimental cell research.

[41]  Joshua T. Burdick,et al.  Mapping determinants of human gene expression by regional and genome-wide association , 2005, Nature.

[42]  Pablo Tamayo,et al.  Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[43]  V. Jobanputra,et al.  A unique case of der(11)t(11;22),‐22 arising from 3:1 segregation of a maternal t(11;22) in a family with co‐segregation of the translocation and breast cancer , 2005, Prenatal diagnosis.

[44]  E. Eichler,et al.  Fine-scale structural variation of the human genome , 2005, Nature Genetics.

[45]  F. Ayala,et al.  Chromosome speciation: Humans, Drosophila, and mosquitoes , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[46]  D. Kleinjan,et al.  Long-range control of gene expression: emerging mechanisms and disruption in disease. , 2005, American journal of human genetics.

[47]  Arcadi Navarro,et al.  Chromosomal rearrangements and the genomic distribution of gene-expression divergence in humans and chimpanzees. , 2004, Trends in genetics : TIG.

[48]  Tom Misteli,et al.  Spatial Positioning A New Dimension in Genome Function , 2004, Cell.

[49]  Cameron S. Osborne,et al.  Active genes dynamically colocalize to shared sites of ongoing transcription , 2004, Nature Genetics.

[50]  Jean YH Yang,et al.  Bioconductor: open software development for computational biology and bioinformatics , 2004, Genome Biology.

[51]  S. Oliver,et al.  Effects of reciprocal chromosomal translocations on the fitness of Saccharomyces cerevisiae , 2004, EMBO reports.

[52]  Gordon K Smyth,et al.  Statistical Applications in Genetics and Molecular Biology Linear Models and Empirical Bayes Methods for Assessing Differential Expression in Microarray Experiments , 2011 .

[53]  C. E. Ford,et al.  The 11q;22q translocation: A European collaborative analysis of 43 cases , 2004, Human Genetics.

[54]  Toshihiro Tanaka.  The International HapMap Project , 2003, Nature.

[55]  Rafael A Irizarry,et al.  Exploration, normalization, and summaries of high density oligonucleotide array probe level data. , 2003, Biostatistics.

[56]  S. Oliver,et al.  Engineering evolution to study speciation in yeasts , 2003, Nature.

[57]  M. Kozubek,et al.  Arrangement of chromosome 11 and 22 territories, EWSR1 and FLI1 genes, and other genetic elements of these chromosomes in human lymphocytes and Ewing sarcoma cells , 2003, Human Genetics.

[58]  Amparo Querol,et al.  Molecular characterization of a chromosomal rearrangement involved in the adaptive evolution of yeast strains. , 2002, Genome research.

[59]  F. Speleman,et al.  Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes , 2002, Genome Biology.

[60]  Thomas D. Schmittgen,et al.  Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. , 2001, Methods.

[61]  B. Emanuel,et al.  Long AT-rich palindromes and the constitutional t(11;22) breakpoint. , 2001, Human molecular genetics.

[62]  Juliet A. Ellis,et al.  The spatial organization of human chromosomes within the nuclei of normal and emerin-mutant cells. , 2001, Human molecular genetics.

[63]  P. Braude,et al.  Successful pregnancy outcomes after preimplantation genetic diagnosis (PGD) for carriers of chromosome translocations , 2001, Human fertility.

[64]  T. Shaikh,et al.  Alu-mediated PCR artifacts and the constitutional t(11;22) breakpoint. , 2000, Human Molecular Genetics.

[65]  E. Zackai,et al.  Tightly clustered 11q23 and 22q11 breakpoints permit PCR-based detection of the recurrent constitutional t(11;22). , 2000, American journal of human genetics.

[66]  Peter Teague,et al.  Differences in the Localization and Morphology of Chromosomes in the Human Nucleus , 1999, The Journal of cell biology.

[67]  D. Ledbetter,et al.  A revision of the lissencephaly and Miller-Dieker syndrome critical regions in chromosome 17p13.3. , 1997, Human molecular genetics.

[68]  D. Jackson,et al.  Active RNA polymerases are localized within discrete transcription "factories' in human nuclei. , 1996, Journal of cell science.

[69]  M. Bittner,et al.  Chromosome arm painting probes , 1996, Nature Genetics.

[70]  Y. Benjamini,et al.  Controlling the false discovery rate: a practical and powerful approach to multiple testing , 1995 .

[71]  C. Larsson,et al.  Predisposition for breast cancer in carriers of constitutional translocation 11q;22q. , 1994, American journal of human genetics.

[72]  D. Warburton,et al.  De novo balanced chromosome rearrangements and extra marker chromosomes identified at prenatal diagnosis: clinical significance and distribution of breakpoints. , 1991, American journal of human genetics.

[73]  E. Zackai,et al.  Site-specific reciprocal translocation, t(11;22) (q23;q11), in several unrelated families with 3:1 meiotic disjunction. , 1980, American journal of medical genetics.