Regional copy number–independent deregulation of transcription in cancer

Genetic and epigenetic alterations have been identified that lead to transcriptional deregulation in cancers. Genetic mechanisms may affect single genes or regions containing several neighboring genes, as has been shown for DNA copy number changes. It was recently reported that epigenetic suppression of gene expression can also extend to a whole region; this is known as long-range epigenetic silencing. Various techniques are available for identifying regional genetic alterations, but no large-scale analysis has yet been carried out to obtain an overview of regional epigenetic alterations. We carried out an exhaustive search for regions susceptible to such mechanisms using a combination of transcriptome correlation map analysis and array CGH data for a series of bladder carcinomas. We validated one candidate region experimentally, demonstrating histone methylation leading to the loss of expression of neighboring genes without DNA methylation.

[1]  W. Rutter,et al.  Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. , 1979, Biochemistry.

[2]  K. Paigen,et al.  A simple, rapid, and sensitive DNA assay procedure. , 1980, Analytical biochemistry.

[3]  M. Knowles,et al.  Simultaneous isolation of DNA, RNA, and antigenic protein exhibiting kinase activity from small tumor samples using guanidine isothiocyanate. , 1990, Analytical biochemistry.

[4]  Nature Genetics , 1991, Nature.

[5]  D. F. Thomas,et al.  Normal human urothelial cells in vitro: proliferation and induction of stratification. , 1994, Laboratory investigation; a journal of technical methods and pathology.

[6]  P. Laird,et al.  COBRA: a sensitive and quantitative DNA methylation assay. , 1997, Nucleic acids research.

[7]  H. Döhner,et al.  Matrix‐based comparative genomic hybridization: Biochips to screen for genomic imbalances , 1997, Genes, chromosomes & cancer.

[8]  A. Hoznek,et al.  Decreased expression of keratinocyte growth factor receptor in a subset of human transitional cell bladder carcinomas , 1997, Oncogene.

[9]  W. Kuo,et al.  High resolution analysis of DNA copy number variation using comparative genomic hybridization to microarrays , 1998, Nature Genetics.

[10]  Y. Nakamura,et al.  Molecular cloning of a candidate tumor suppressor gene, DLC1, from chromosome 3p21.3. , 1999, Cancer research.

[11]  Hongyue Dai,et al.  Widespread aneuploidy revealed by DNA microarray expression profiling , 2000, Nature Genetics.

[12]  G. Church,et al.  A computational analysis of whole-genome expression data reveals chromosomal domains of gene expression , 2000, Nature Genetics.

[13]  B. Turner,et al.  Cellular Memory and the Histone Code , 2002, Cell.

[14]  R. Strausberg,et al.  A preliminary transcriptome map of non-small cell lung cancer. , 2002, Cancer research.

[15]  W. J. Kent,et al.  BLAT--the BLAST-like alignment tool. , 2002, Genome research.

[16]  Ajay N. Jain,et al.  Fully automatic quantification of microarray image data. , 2002, Genome research.

[17]  M. Ringnér,et al.  Impact of DNA amplification on gene expression patterns in breast cancer. , 2002, Cancer research.

[18]  Christian A. Rees,et al.  Microarray analysis reveals a major direct role of DNA copy number alteration in the transcriptional program of human breast tumors , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[19]  Peter A. Jones,et al.  Histone H3-lysine 9 methylation is associated with aberrant gene silencing in cancer cells and is rapidly reversed by 5-aza-2'-deoxycytidine. , 2002, Cancer research.

[20]  A. Bird.  DNA methylation patterns and epigenetic memory. , 2002, Genes & development.

[21]  Colin C. Collins,et al.  Integrated genomic and epigenomic analyses pinpoint biallelic gene inactivation in tumors , 2002, Nature Genetics.

[22]  Gerald M Rubin,et al.  Evidence for large domains of similarly expressed genes in the Drosophila genome , 2002, Journal of biology.

[23]  K. Furge,et al.  Identification of frequent cytogenetic aberrations in hepatocellular carcinoma using gene-expression microarray data , 2002, Genome Biology.

[24]  S. Nishikawa,et al.  Phospholipase Cδ1 is required for skin stem cell lineage commitment , 2003 .

[25]  R. van Driel,et al.  The eukaryotic genome: a system regulated at different hierarchical levels , 2003, Journal of Cell Science.

[26]  S. Nishikawa,et al.  Phospholipase Cdelta1 is required for skin stem cell lineage commitment. , 2003, The EMBO journal.

[27]  Thomas D. Wu,et al.  Genome-wide identification of chromosomal regions of increased tumor expression by transcriptome analysis. , 2003, Cancer research.

[28]  S. Ishikawa,et al.  Expression imbalance map: a new visualization method for detection of mRNA expression imbalance regions. , 2003, Physiological genomics.

[29]  B. Turner,et al.  Immunoprecipitation of native chromatin: NChIP. , 2003, Methods.

[30]  Ajay N. Jain,et al.  Genome-wide-array-based comparative genomic hybridization reveals genetic homogeneity and frequent copy number increases encompassing CCNE1 in Fallopian tube carcinoma , 2003, Oncogene.

[31]  Ash A. Alizadeh,et al.  Gene Expression Signature of Fibroblast Serum Response Predicts Human Cancer Progression: Similarities between Tumors and Wounds , 2004, PLoS biology.

[32]  Jonathan Pevsner,et al.  Gene expression alterations over large chromosomal regions in cancers include multiple genes unrelated to malignant progression. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[33]  Emmanuel Barillot,et al.  Analysis of array CGH data: from signal ratio to gain and loss of DNA regions , 2004, Bioinform..

[34]  W. Bickmore,et al.  Chromatin decondensation and nuclear reorganization of the HoxB locus upon induction of transcription. , 2004, Genes & development.

[35]  C. Pál,et al.  The evolutionary dynamics of eukaryotic gene order , 2004, Nature Reviews Genetics.

[36]  Kunihiro Nishimura,et al.  Distinct Chromosomal Bias of Gene Expression Signatures in the Progression of Hepatocellular Carcinoma , 2004, Cancer Research.

[37]  Bin Tean Teh,et al.  A molecular classification of papillary renal cell carcinoma. , 2005, Cancer research.

[38]  Nicolas Stransky,et al.  Visualizing chromosomes as transcriptome correlation maps: evidence of chromosomal domains containing co-expressed genes--a study of 130 invasive ductal breast carcinomas. , 2005, Cancer research.

[39]  Yu Shyr,et al.  Coupled analysis of gene expression and chromosomal location. , 2005, Genomics.

[40]  B. Bernstein,et al.  Genomic views of chromatin. , 2005, Current opinion in genetics & development.

[41]  Karl J. Dykema,et al.  Comparison of array-based comparative genomic hybridization with gene expression-based regional expression biases to identify genetic abnormalities in hepatocellular carcinoma , 2005, BMC Genomics.

[42]  Emmanuel Barillot,et al.  Spatial normalization of array-CGH data , 2006, BMC Bioinformatics.

[43]  Mattias Höglund,et al.  Microarray analyses reveal strong influence of DNA copy number alterations on the transcriptional patterns in pancreatic cancer: implications for the interpretation of genomic amplifications , 2005, Oncogene.

[44]  Nick Gilbert,et al.  The role of chromatin structure in regulating the expression of clustered genes , 2005, Nature Reviews Genetics.

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

[46]  A. Kretsovali,et al.  Coordinated changes of histone modifications and HDAC mobilization regulate the induction of MHC class II genes by Trichostatin A , 2006, Nucleic acids research.