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Mapping of genetic and epigenetic regulatory networks using microarrays

Nature Genetics volume 37, pages S18–S24 (2005)Cite this article

Abstract

The highly coordinated expression of thousands of genes in an organism is regulated by the concerted action of hundreds of transcription factors and chromatin proteins, as well as by epigenetic mechanisms. Understanding the architecture of these vastly complex regulatory networks is one of the main challenges in the postgenomic era. New microarray-based techniques have become available for the genome-wide mapping of in vivo protein-DNA interactions and epigenetic marks. Data sets obtained with these techniques begin to offer the first comprehensive views of genetic and epigenetic regulatory networks.

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Figure 1
Figure 2: Principles of two microarray-based methods for mapping protein-genome interactions: (a) ChIP-chip and (b) DamID.
Figure 3: Graph representation of a hypothetical transcription factor regulatory network.
Figure 4: Distribution of dimethylation at Lys4 of H3 (H3K9me2) in the human genome.

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References

  1. Jaenisch, R. & Bird, A. Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nat. Genet. 33 Suppl., 245–254 (2003).

    Article  CAS  PubMed  Google Scholar 

  2. Jenuwein, T. & Allis, C.D. Translating the histone code. Science 293, 1074–1080 (2001).

    Article  CAS  PubMed  Google Scholar 

  3. Peterson, C.L. & Laniel, M.A. Histones and histone modifications. Curr. Biol. 14, R546–R551 (2004).

    Article  CAS  PubMed  Google Scholar 

  4. Phair, R.D. et al. Global nature of dynamic protein-chromatin interactions in vivo: three-dimensional genome scanning and dynamic interaction networks of chromatin proteins. Mol. Cell Biol. 24, 6393–6402 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Weinmann, A.S. & Farnham, P.J. Identification of unknown target genes of human transcription factors using chromatin immunoprecipitation. Methods 26, 37–47 (2002).

    Article  CAS  PubMed  Google Scholar 

  6. Robyr, D., Kurdistani, S.K. & Grunstein, M. Analysis of genome-wide histone acetylation state and enzyme binding using DNA microarrays. Methods Enzymol. 376, 289–304 (2004).

    Article  CAS  PubMed  Google Scholar 

  7. Ren, B. & Dynlacht, B.D. Use of chromatin immunoprecipitation assays in genome-wide location analysis of mammalian transcription factors. Methods Enzymol. 376, 304–315 (2004).

    Article  CAS  PubMed  Google Scholar 

  8. van Steensel, B. & Henikoff, S. Identification of in vivo DNA targets of chromatin proteins using tethered dam methyltransferase. Nat. Biotechnol. 18, 424–428 (2000).

    Article  CAS  PubMed  Google Scholar 

  9. van Steensel, B., Delrow, J. & Henikoff, S. Chromatin profiling using targeted DNA adenine methyltransferase. Nat. Genet. 27, 304–308 (2001).

    Article  CAS  PubMed  Google Scholar 

  10. van Steensel, B. & Henikoff, S. Epigenomic profiling using microarrays. Biotechniques 35, 346–350, 352–354, 356–357 (2003).

    Article  CAS  PubMed  Google Scholar 

  11. Lodén, M. & van Steensel, B. Whole-genome views of chromatin structure. Chrom. Res. (in the press).

  12. Sun, L.V. et al. Protein-DNA interaction mapping using genomic tiling path microarrays in Drosophila. Proc. Natl. Acad. Sci. USA 100, 9428–9433 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Lippman, Z. et al. Role of transposable elements in heterochromatin and epigenetic control. Nature 430, 471–476 (2004).

    Article  CAS  PubMed  Google Scholar 

  14. Hatada, I. et al. A microarray-based method for detecting methylated loci. J. Hum. Genet. 47, 448–451 (2002).

    Article  CAS  PubMed  Google Scholar 

  15. Tompa, R. et al. Genome-wide profiling of DNA methylation reveals transposon targets of CHROMOMETHYLASE3. Curr. Biol. 12, 65–68 (2002).

    Article  CAS  PubMed  Google Scholar 

  16. Yan, P.S. et al. Dissecting complex epigenetic alterations in breast cancer using CpG island microarrays. Cancer Res. 61, 8375–8380 (2001).

    CAS  PubMed  Google Scholar 

  17. Wei, S.H. et al. Methylation microarray analysis of late-stage ovarian carcinomas distinguishes progression-free survival in patients and identifies candidate epigenetic markers. Clin. Cancer Res. 8, 2246–2252 (2002).

    CAS  PubMed  Google Scholar 

  18. Adorjan, P. et al. Tumour class prediction and discovery by microarray-based DNA methylation analysis. Nucleic Acids Res. 30, e21 (2002).

    Article  PubMed  PubMed Central  Google Scholar 

  19. Gitan, R.S., Shi, H., Chen, C.M., Yan, P.S. & Huang, T.H. Methylation-specific oligonucleotide microarray: a new potential for high-throughput methylation analysis. Genome Res. 12, 158–164 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Ren, B. et al. Genome-wide location and function of DNA binding proteins. Science 290, 2306–2309 (2000).

    Article  CAS  PubMed  Google Scholar 

  21. Lieb, J.D., Liu, X., Botstein, D. & Brown, P.O. Promoter-specific binding of Rap1 revealed by genome-wide maps of protein-DNA association. Nat. Genet. 28, 327–334 (2001).

    Article  CAS  PubMed  Google Scholar 

  22. Lee, T.I. et al. Transcriptional regulatory networks in Saccharomyces cerevisiae. Science 298, 799–804 (2002).

    Article  CAS  PubMed  Google Scholar 

  23. Iyer, V.R. et al. Genomic binding sites of the yeast cell-cycle transcription factors SBF and MBF. Nature 409, 533–538 (2001).

    Article  CAS  PubMed  Google Scholar 

  24. Harbison, C.T. et al. Transcriptional regulatory code of a eukaryotic genome. Nature 431, 99–104 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Cam, H. et al. A common set of gene regulatory networks links metabolism and growth inhibition. Mol. Cell 16, 399–411 (2004).

    Article  CAS  PubMed  Google Scholar 

  26. Blais, A. et al. An initial blueprint for myogenic differentiation. Genes Dev. 19, 553–569 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Ren, B. et al. E2F integrates cell cycle progression with DNA repair, replication, and G(2)/M checkpoints. Genes Dev. 16, 245–256 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Odom, D.T. et al. Control of pancreas and liver gene expression by HNF transcription factors. Science 303, 1378–1381 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Li, Z. et al. A global transcriptional regulatory role for c-Myc in Burkitt's lymphoma cells. Proc. Natl. Acad. Sci. USA 100, 8164–8169 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Fernandez, P.C. et al. Genomic targets of the human c-Myc protein. Genes Dev. 17, 1115–1129 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Orian, A. et al. Genomic binding by the Drosophila Myc, Max, Mad/Mnt transcription factor network. Genes Dev. 17, 1101–1114 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. van Steensel, B., Delrow, J. & Bussemaker, H.J. Genomewide analysis of Drosophila GAGA factor target genes reveals context-dependent DNA binding. Proc. Natl. Acad. Sci. USA 100, 2580–2585 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Cawley, S. et al. Unbiased mapping of transcription factor binding sites along human chromosomes 21 and 22 points to widespread regulation of noncoding RNAs. Cell 116, 499–509 (2004).

    Article  CAS  PubMed  Google Scholar 

  34. Euskirchen, G. et al. CREB binds to multiple loci on human chromosome 22. Mol. Cell Biol. 24, 3804–3814 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Martone, R. et al. Distribution of NF-kappaB-binding sites across human chromosome 22. Proc. Natl. Acad. Sci. USA 100, 12247–12252 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Zeitlinger, J. et al. Program-specific distribution of a transcription factor dependent on partner transcription factor and MAPK signaling. Cell 113, 395–404 (2003).

    Article  CAS  PubMed  Google Scholar 

  37. Wells, J., Yan, P.S., Cechvala, M., Huang, T. & Farnham, P.J. Identification of novel pRb binding sites using CpG microarrays suggests that E2F recruits pRb to specific genomic sites during S phase. Oncogene 22, 1445–1460 (2003).

    Article  CAS  PubMed  Google Scholar 

  38. Robert, F. et al. Global position and recruitment of HATs and HDACs in the yeast genome. Mol. Cell 16, 199–209 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Bianchi-Frias, D. et al. Hairy transcriptional repression targets and cofactor recruitment in Drosophila. PLoS. Biol. 2, E178 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  40. Simon, I. et al. Serial regulation of transcriptional regulators in the yeast cell cycle. Cell 106, 697–708 (2001).

    Article  CAS  PubMed  Google Scholar 

  41. Tran, R.K. et al. DNA methylation profiling identifies CG methylation clusters in Arabidopsis genes. Curr. Biol. 15, 154–159 (2005).

    Article  CAS  PubMed  Google Scholar 

  42. Shi, H. et al. Triple analysis of the cancer epigenome: an integrated microarray system for assessing gene expression, DNA methylation, and histone acetylation. Cancer Res. 63, 2164–2171 (2003).

    CAS  PubMed  Google Scholar 

  43. Leu, Y.W. et al. Loss of estrogen receptor signaling triggers epigenetic silencing of downstream targets in breast cancer. Cancer Res. 64, 8184–8192 (2004).

    Article  CAS  PubMed  Google Scholar 

  44. Ballestar, E. et al. Methyl-CpG binding proteins identify novel sites of epigenetic inactivation in human cancer. EMBO J. 22, 6335–6345 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Schübeler, D. et al. The histone modification pattern of active genes revealed through genome-wide chromatin analysis of a higher eukaryote. Genes Dev. 18, 1263–1271 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  46. Schreiber, S.L. & Bernstein, B.E. Signaling network model of chromatin. Cell 111, 771–778 (2002).

    Article  CAS  PubMed  Google Scholar 

  47. Kurdistani, S.K., Tavazoie, S. & Grunstein, M. Mapping global histone acetylation patterns to gene expression. Cell 117, 721–733 (2004).

    Article  CAS  PubMed  Google Scholar 

  48. Robyr, D. et al. Microarray deacetylation maps determine genome-wide functions for yeast histone deacetylases. Cell 109, 437–446 (2002).

    Article  CAS  PubMed  Google Scholar 

  49. Kurdistani, S.K., Robyr, D., Tavazoie, S. & Grunstein, M. Genome-wide binding map of the histone deacetylase Rpd3 in yeast. Nat. Genet. 31, 248–254 (2002).

    Article  CAS  PubMed  Google Scholar 

  50. Humphrey, E.L., Shamji, A.F., Bernstein, B.E. & Schreiber, S.L. Rpd3p relocation mediates a transcriptional response to rapamycin in yeast. Chem. Biol. 11, 295–299 (2004).

    Article  CAS  PubMed  Google Scholar 

  51. Bernstein, B.E. et al. Genomic maps and comparative analysis of histone modifications in human and mouse. Cell 120, 169–181 (2005).

    Article  CAS  PubMed  Google Scholar 

  52. Henikoff, S., Furuyama, T. & Ahmad, K. Histone variants, nucleosome assembly and epigenetic inheritance. Trends Genet. 20, 320–326 (2004).

    Article  CAS  PubMed  Google Scholar 

  53. Bernstein, B.E., Liu, C.L., Humphrey, E.L., Perlstein, E.O. & Schreiber, S.L. Global nucleosome occupancy in yeast. Genome Biol. 5, R62 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  54. Lee, C.K., Shibata, Y., Rao, B., Strahl, B.D. & Lieb, J.D. Evidence for nucleosome depletion at active regulatory regions genome-wide. Nat. Genet. 36, 900–905 (2004).

    Article  CAS  PubMed  Google Scholar 

  55. Jackson, J.P., Lindroth, A.M., Cao, X. & Jacobsen, S.E. Control of CpNpG DNA methylation by the KRYPTONITE histone H3 methyltransferase. Nature 416, 556–560 (2002).

    Article  CAS  PubMed  Google Scholar 

  56. Greil, F. et al. Distinct HP1 and Su(var)3-9 complexes bind to sets of developmentally coexpressed genes depending on chromosomal location. Genes Dev. 17, 2825–2838 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Kirmizis, A. et al. Silencing of human polycomb target genes is associated with methylation of histone H3 Lys 27. Genes Dev. 18, 1592–1605 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Nuwaysir, E.F. et al. Gene expression analysis using oligonucleotide arrays produced by maskless photolithography. Genome Res. 12, 1749–1755 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Rakyan, V.K. et al. DNA methylation profiling of the human major histocompatibility complex: a pilot study for the human epigenome project. PLoS. Biol. 2, e405 (2004).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  60. Kim, J., Bhinge, A.A., Morgan, X.C. & Iyer, V.R. Mapping DNA-protein interactions in large genomes by sequence tag analysis of genomic enrichment. Nat. Methods 2, 47–53 (2005).

    Article  CAS  PubMed  Google Scholar 

  61. Stolc, V. et al. A gene expression map for the euchromatic genome of Drosophila melanogaster. Science 306, 655–660 (2004).

    Article  CAS  PubMed  Google Scholar 

  62. Bertone, P. et al. Global identification of human transcribed sequences with genome tiling arrays. Science 306, 2242–2246 (2004).

    Article  CAS  PubMed  Google Scholar 

  63. Gilbert, N. et al. Chromatin architecture of the human genome: gene-rich domains are enriched in open chromatin fibers. Cell 118, 555–566 (2004).

    Article  CAS  PubMed  Google Scholar 

  64. Weil, M.R., Widlak, P., Minna, J.D. & Garner, H.R. Global survey of chromatin accessibility using DNA microarrays. Genome Res. 14, 1374–1381 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. The ENCODE Project Consortium. The ENCODE (ENCyclopedia Of DNA Elements) Project. Science 306, 636–640 (2004).

  66. Liu, X.S., Brutlag, D.L. & Liu, J.S. An algorithm for finding protein-DNA binding sites with applications to chromatin-immunoprecipitation microarray experiments. Nat. Biotechnol. 20, 835–839 (2002).

    Article  CAS  PubMed  Google Scholar 

  67. Bussemaker, H.J., Li, H. & Siggia, E.D. Regulatory element detection using correlation with expression. Nat. Genet. 27, 167–171 (2001).

    Article  CAS  PubMed  Google Scholar 

  68. Roth, F.P., Hughes, J.D., Estep, P.W. & Church, G.M. Finding DNA regulatory motifs within unaligned noncoding sequences clustered by whole-genome mRNA quantitation. Nat. Biotechnol. 16, 939–945 (1998).

    Article  CAS  PubMed  Google Scholar 

  69. Babu, M.M., Luscombe, N.M., Aravind, L., Gerstein, M. & Teichmann, S.A. Structure and evolution of transcriptional regulatory networks. Curr. Opin. Struct. Biol. 14, 283–291 (2004).

    Article  CAS  PubMed  Google Scholar 

  70. Chinnaiyan, A. Integrative analysis of the cancer transcriptome Nat. Genet. 37, 31–37 (2005).

    Article  CAS  Google Scholar 

  71. Koller, D. From signatures to models: understanding cancer using microarrays. Nat. Genet. 37, 38–45 (2005).

    Article  CAS  Google Scholar 

  72. Beer, M.A. & Tavazoie, S. Predicting gene expression from sequence. Cell 117, 185–198 (2004).

    Article  CAS  PubMed  Google Scholar 

  73. Bar-Joseph, Z. et al. Computational discovery of gene modules and regulatory networks. Nat. Biotechnol. 21, 1337–1342 (2003).

    Article  CAS  PubMed  Google Scholar 

  74. Gao, F., Foat, B.C. & Bussemaker, H.J. Defining transcriptional networks through integrative modeling of mRNA expression and transcription factor binding data. BMC Bioinformatics 5, 31 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  75. Setty, Y., Mayo, A.E., Surette, M.G. & Alon, U. Detailed map of a cis-regulatory input function. Proc. Natl. Acad. Sci. USA 100, 7702–7707 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

I thank M. Wolkers, F. van Leeuwen, D. Schübeler and members of my laboratory for suggestions. This work was supported by the Human Frontier Science Program, NWO-Genomics, the Dutch Cancer Society and an EURYI Award.

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  1. the Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam, 1066 CX, The Netherlands

    Bas van Steensel

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B.v.S. is listed as an inventor on a patent application that was filed for the DamID technology.

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van Steensel, B. Mapping of genetic and epigenetic regulatory networks using microarrays. Nat Genet 37 (Suppl 6), S18–S24 (2005). https://doi.org/10.1038/ng1559

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