Epigenomics: beyond CpG islands

Epigenomic studies aim to define the location and nature of the genomic sequences that are epigenetically modified. Much progress has been made towards whole-genome epigenetic profiling using molecular techniques, but the analysis of such large and complex data sets is far from trivial given the correlated nature of sequence and functional characteristics within the genome. We describe the statistical solutions that help to overcome the problems with data-set complexity, in anticipation of the imminent wealth of data that will be generated by new genome-wide epigenetic profiling and DNA sequence analysis techniques. So far, epigenomic studies have succeeded in identifying CpG islands, but recent evidence points towards a role for transposable elements in epigenetic regulation, causing the fields of study of epigenetics and transposable element biology to converge.

[1]  H. Lauke,et al.  Cell Type-specific Expression of LINE-1 Open Reading Frames 1 and 2 in Fetal and Adult Human Tissues* , 2004, Journal of Biological Chemistry.

[2]  G. Bernardi,et al.  Correlations between isochores and chromosomal bands in the human genome. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[3]  K. Strauch,et al.  Linkage Analysis of Asthma and Atopy Including Models with Genomic Imprinting , 2001, Genetic epidemiology.

[4]  Andrew Collins,et al.  The distinguishing sequence characteristics of mouse imprinted genes , 2002, Mammalian Genome.

[5]  John M. Greally,et al.  Short interspersed transposable elements (SINEs) are excluded from imprinted regions in the human genome , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[6]  A. Bird,et al.  Methylation-Induced Repression— Belts, Braces, and Chromatin , 1999, Cell.

[7]  C. Allis,et al.  Parent-specific complementary patterns of histone H3 lysine 9 and H3 lysine 4 methylation at the Prader-Willi syndrome imprinting center. , 2001, American journal of human genetics.

[8]  International Human Genome Sequencing Consortium.  Initial sequencing and analysis of the human genome , 2001, Nature.

[9]  Arian F. A. Smit,et al.  MIRs are classic, tRNA-derived SINEs that amplified before the mammalian radiation , 1995, Nucleic Acids Res..

[10]  Robert C. Wolpert,et al.  A Review of the , 1985 .

[11]  D. Gudbjartsson,et al.  A high-resolution recombination map of the human genome , 2002, Nature Genetics.

[12]  C. Allis,et al.  Histone acetyltransferases. , 2001, Annual review of biochemistry.

[13]  Jason R. Clark,et al.  Enzymes by post—restriction enzyme stability , 2000, Nature Biotechnology.

[14]  C. Walsh,et al.  Cytosine methylation and the ecology of intragenomic parasites. , 1997, Trends in genetics : TIG.

[15]  V. Ingram,et al.  Differentiation of two mouse cell lines is associated with hypomethylation of their genomes , 1984, Molecular and cellular biology.

[16]  Shirley M. Tilghman,et al.  CTCF mediates methylation-sensitive enhancer-blocking activity at the H19/Igf2 locus , 2000, Nature.

[17]  Mary C. Rykowski,et al.  Human genome organization: Alu, LINES, and the molecular structure of metaphase chromosome bands , 1988, Cell.

[18]  R. Scott,et al.  From expressed sequence tags to 'epigenomics': an understanding of disease processes. , 1997, Current Opinion in Biotechnology.

[19]  Christoph Plass,et al.  Cancer epigenomics. , 2002, Human molecular genetics.

[20]  D. Riesner,et al.  Induction of Tumors in Mice by Genomic Hypomethylation , 2003 .

[21]  N. Okada,et al.  SINEs and LINEs share common 3' sequences: a review. , 1997, Gene.

[22]  Wendy A. Bickmore,et al.  The distribution of CpG islands in mammalian chromosomes , 1994, Nature Genetics.

[23]  Eva K. Lee,et al.  Predicting aberrant CpG island methylation , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[24]  D. Higgs,et al.  The pattern of replication at a human telomeric region (16p13.3): its relationship to chromosome structure and gene expression. , 1999, Human molecular genetics.

[25]  L. Mahadevan,et al.  Independent dynamic regulation of histone phosphorylation and acetylation during immediate-early gene induction. , 2001, Molecular cell.

[26]  D. Ward,et al.  Chromosomal and nuclear distribution of the HindIII 1.9-kb human DNA repeat segment , 2004, Chromosoma.

[27]  R. Sinsheimer.  The action of pancreatic deoxyribonuclease. II. Isomeric dinucleotides. , 1955, The Journal of biological chemistry.

[28]  S. Rastan,et al.  The search for the mouse X-chromosome inactivation centre. , 1990, Genetical research.

[29]  Robert L. Tanguay,et al.  In vivo footprint and methylation analysis by PCR-aided genomic sequencing: comparison of active and inactive X chromosomal DNA at the CpG island and promoter of human PGK-1. , 1990, Genes & development.

[30]  Jef D Boeke,et al.  Human L1 Retrotransposon Encodes a Conserved Endonuclease Required for Retrotransposition , 1996, Cell.

[31]  S. Beck,et al.  From genomics to epigenomics: a loftier view of life , 1999, Nature Biotechnology.

[32]  C. Schmid,et al.  Alu repeated DNAs are differentially methylated in primate germ cells. , 1994, Nucleic acids research.

[33]  M. Lyon,et al.  X-Chromosome inactivation: a repeat hypothesis , 1998, Cytogenetic and Genome Research.

[34]  Jeffrey H. Miller,et al.  Mutagenic deamination of cytosine residues in DNA , 1980, Nature.

[35]  T. Ashley.  G-band position effects on meiotic synapsis and crossing over. , 1988, Genetics.

[36]  Daiya Takai,et al.  Comprehensive analysis of CpG islands in human chromosomes 21 and 22 , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[37]  M. Turker,et al.  Tandem B1 Elements Located in a Mouse Methylation Center Provide a Target for de Novo DNA Methylation* , 1999, The Journal of Biological Chemistry.

[38]  X. Ke,et al.  A novel approach for identifying candidate imprinted genes through sequence analysis of imprinted and control genes , 2002, Human Genetics.

[39]  J. D. Engel,et al.  Beta-globin YAC transgenes exhibit uniform expression levels but position effect variegation in mice. , 2000, Human molecular genetics.

[40]  T. Smith,et al.  A fundamental division in the Alu family of repeated sequences. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[41]  Michael Q. Zhang,et al.  A global transcriptional regulatory role for c-Myc in Burkitt's lymphoma cells , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[42]  J. Jurka,et al.  Duplication, coclustering, and selection of human Alu retrotransposons. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[43]  J. Herman,et al.  Aberrant patterns of DNA methylation, chromatin formation and gene expression in cancer. , 2001, Human molecular genetics.

[44]  M. Frommer,et al.  CpG islands in vertebrate genomes. , 1987, Journal of molecular biology.

[45]  S. Boissinot,et al.  Selection against deleterious LINE-1-containing loci in the human lineage. , 2001, Molecular biology and evolution.

[46]  A. Bird.  DNA methylation and the frequency of CpG in animal DNA. , 1980, Nucleic acids research.

[47]  Danny Reinberg,et al.  Histone lysine methylation: a signature for chromatin function. , 2003, Trends in genetics : TIG.

[48]  D. Botstein,et al.  Genome-wide scan of bipolar disorder in 65 pedigrees: supportive evidence for linkage at 8q24, 18q22, 4q32, 2p12, and 13q12 , 2003, Molecular Psychiatry.

[49]  G. Bernardi,et al.  Compositional compartmentalization and compositional patterns in the nuclear genomes of plants. , 1988, Nucleic acids research.

[50]  Thomas E. Royce,et al.  Distribution of NF-κB-binding sites across human chromosome 22 , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[51]  U. Francke,et al.  In vivo nuclease hypersensitivity studies reveal multiple sites of parental origin-dependent differential chromatin conformation in the 150 kb SNRPN transcription unit. , 1999, Human molecular genetics.

[52]  N. Hattori,et al.  Genome-wide analysis of DNA methylation status of CpG islands in embryoid bodies, teratomas, and fetuses. , 2003, Biochemical and biophysical research communications.

[53]  G. Bernardi,et al.  Gene density in the Giemsa bands of human chromosomes , 2004, Chromosome Research.

[54]  Rudolf Jaenisch,et al.  Role for DNA methylation in genomic imprinting , 1993, Nature.

[55]  P. Parfrey,et al.  Impact of Gender and Parent of Origin on the Phenotypic Expression of Hereditary Nonpolyposis Colorectal Cancer in a Large Newfoundland Kindred With a Common MSH2 Mutation , 2002, Diseases of the colon and rectum.

[56]  D. Gudbjartsson,et al.  A susceptibility gene for psoriatic arthritis maps to chromosome 16q: evidence for imprinting. , 2003, American journal of human genetics.

[57]  Tom H. Pringle,et al.  The human genome browser at UCSC. , 2002, Genome research.

[58]  T. Moore,et al.  Imprinted genes have few and small introns , 1996, Nature Genetics.

[59]  Anne Bergmann,et al.  Methylation-sensitive binding of transcription factor YY1 to an insulator sequence within the paternally expressed imprinted gene, Peg3. , 2003, Human molecular genetics.

[60]  D C Ward,et al.  Differential distribution of long and short interspersed element sequences in the mouse genome: chromosome karyotyping by fluorescence in situ hybridization. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[61]  C. Allis,et al.  Translating the Histone Code , 2001, Science.

[62]  Stilianos Arhondakis,et al.  Base composition and expression level of human genes. , 2004, Gene.

[63]  S. Saitoh,et al.  Parent-of-origin specific histone acetylation and reactivation of a key imprinted gene locus in Prader-Willi syndrome. , 2000, American journal of human genetics.

[64]  Pearlly S Yan,et al.  Identification of novel pRb binding sites using CpG microarrays suggests that E2F recruits pRb to specific genomic sites during S phase , 2003, Oncogene.

[65]  S. Cawley,et al.  Unbiased Mapping of Transcription Factor Binding Sites along Human Chromosomes 21 and 22 Points to Widespread Regulation of Noncoding RNAs , 2004, Cell.

[66]  G Bernardi,et al.  Methylation patterns in the isochores of vertebrate genomes. , 1997, Gene.

[67]  M. Peinado,et al.  Methylome profiling of cancer cells by amplification of inter-methylated sites (AIMS). , 2002, Nucleic acids research.

[68]  C. Schmid,et al.  Developmental differences in methylation of human Alu repeats , 1993, Molecular and cellular biology.

[69]  S. Rich,et al.  Examination of candidate chromosomal regions for type 2 diabetes reveals a susceptibility locus on human chromosome 8p23.1. , 2004, Diabetes.

[70]  G Bernardi,et al.  CpG doublets, CpG islands and Alu repeats in long human DNA sequences from different isochore families. , 1998, Gene.

[71]  M. Oshimura,et al.  Use of real-time RT-PCR for the detection of allelic expression of an imprinted gene. , 2003, International journal of molecular medicine.

[72]  Tim Hui-Ming Huang,et al.  Methylation target array for rapid analysis of CpG island hypermethylation in multiple tissue genomes. , 2003, The American journal of pathology.

[73]  Satoshi Tanaka,et al.  Epigenetic marks by DNA methylation specific to stem, germ and somatic cells in mice , 2002, Genes to cells : devoted to molecular & cellular mechanisms.

[74]  S Beck,et al.  Epigenomics: genome-wide study of methylation phenomena. , 2002, Current issues in molecular biology.

[75]  Mark Gerstein,et al.  Distribution of NF-kappaB-binding sites across human chromosome 22. , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[76]  T. Huang,et al.  Methylation profiling of CpG islands in human breast cancer cells. , 1999, Human molecular genetics.

[77]  S. Fiering,et al.  Position Effects Are Influenced by the Orientation of a Transgene with Respect to Flanking Chromatin , 2001, Molecular and Cellular Biology.

[78]  W Dean,et al.  Mammalian epigenomics: reprogramming the genome for development and therapy. , 2003, Theriogenology.

[79]  Tim Hui-Ming Huang,et al.  Applications of CpG island microarrays for high-throughput analysis of DNA methylation. , 2002, The Journal of nutrition.

[80]  Peter Kraft,et al.  High concentrations of long interspersed nuclear element sequence distinguish monoallelically expressed genes , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[81]  Yi Zhang.  Transcriptional regulation by histone ubiquitination and deubiquitination. , 2003, Genes & development.

[82]  J. Lieb,et al.  ChIP-chip: considerations for the design, analysis, and application of genome-wide chromatin immunoprecipitation experiments. , 2004, Genomics.

[83]  K. Kinzler,et al.  Genetic instabilities in human cancers , 1998, Nature.

[84]  A. Bird.  CpG-rich islands and the function of DNA methylation , 1986, Nature.

[85]  R. Deberardinis,et al.  A mouse model of human L1 retrotransposition , 2002, Nature Genetics.

[86]  G. Bernardi,et al.  Compositional patterns in vertebrate genomes: Conservation and change in evolution , 2005, Journal of Molecular Evolution.

[87]  J A Bailey,et al.  Molecular evidence for a relationship between LINE-1 elements and X chromosome inactivation: the Lyon repeat hypothesis. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[88]  J. Bradbury,et al.  Human Epigenome Project—Up and Running , 2003, PLoS biology.

[89]  Susan J. Clark,et al.  CpNpG methylation in mammalian cells , 1995, Nature Genetics.

[90]  Tim Hui-Ming Huang,et al.  Isolating human transcription factor targets by coupling chromatin immunoprecipitation and CpG island microarray analysis. , 2002, Genes & development.

[91]  J. K. Day,et al.  Genistein alters methylation patterns in mice. , 2002, The Journal of nutrition.

[92]  Michael Q. Zhang,et al.  Large-scale human promoter mapping using CpG islands , 2000, Nature Genetics.

[93]  V. Chapman,et al.  Genetic mapping and systematic screening of mouse endogenously imprinted loci detected with restriction landmark genome scanning method (RLGS) , 1994, Mammalian Genome.

[94]  E. Whitelaw,et al.  The vagaries of variegating transgenes. , 1996, BioEssays : news and reviews in molecular, cellular and developmental biology.

[95]  W. Schulz,et al.  Enhancement of reporter gene de novo methylation by DNA fragments from the alpha-fetoprotein control region. , 1994, The Journal of biological chemistry.

[96]  A Collins,et al.  CpG Islands in Human X‐Inactivation , 2003, Annals of human genetics.

[97]  A. Riggs,et al.  Methylation of mouse liver DNA studied by means of the restriction enzymes msp I and hpa II. , 1979, Science.

[98]  G. Bernardi,et al.  Similar integration but different stability of Alus and LINEs in the human genome. , 2001, Gene.

[99]  A. Razin,et al.  Methylation of CpG sequences in eukaryotic DNA , 1981, FEBS letters.

[100]  S. Kochanek,et al.  Transcriptional silencing of human Alu sequences and inhibition of protein binding in the box B regulatory elements by 5′‐CG‐3′ methylation , 1995, FEBS letters.

[101]  W. Reik,et al.  Genomic imprinting: parental influence on the genome , 2001, Nature Reviews Genetics.

[102]  L. Duret,et al.  Determinants of CpG islands: expression in early embryo and isochore structure. , 2001, Genome research.

[103]  R. Jaenisch,et al.  Induction of Tumors in Mice by Genomic Hypomethylation , 2003, Science.