##common.pageHeaderLogo.altText##

Review article: Biomedical intelligence

Vol. 147 No. 4142 (2017)

Genetic determinants of the epigenome in development and cancer

  • Adrian Bird
Cite this as:
Swiss Med Wkly. 2017;147:w14523
Published
12.10.2017

Summary

Although we have detailed maps of epigenetic marks on DNA and chromatin for many cell types and disease states, the origin and significance of these patterns is incompletely understood. Deregulation of the epigenome is a frequent accompaniment to cancer, and it is therefore important that we learn how it contributes to tumour formation. Here it is proposed that the roles of DNA sequence signals as determinants of the epigenome have been underappreciated. Taking as a paradigm the part played by the dinucleotide CpG in regulating gene expression via its effects on the epigenome, it is suggested that factors recognising other short, frequent sequence motifs also recruit chromatin modifying enzymes in response to DNA sequence. A screen for factors of this kind promises to aid our understanding of the mechanisms by which gene activity is globally regulated.

References

  1. Ebrahimi B. Reprogramming barriers and enhancers: strategies to enhance the efficiency and kinetics of induced pluripotency. Cell Regen (Lond). 2015;4(1):10.https://doi.org/10.1186/s13619-015-0024-9
  2. Berman BP, Weisenberger DJ, Aman JF, Hinoue T, Ramjan Z, Liu Y, et al. Regions of focal DNA hypermethylation and long-range hypomethylation in colorectal cancer coincide with nuclear lamina-associated domains. Nat Genet. 2011;44(1):40–6.https://doi.org/10.1038/ng.969
  3. Bird AP. CpG-rich islands and the function of DNA methylation. Nature. 1986;321(6067):209–13.https://doi.org/10.1038/321209a0
  4. Macleod D, Charlton J, Mullins J, Bird AP. Sp1 sites in the mouse aprt gene promoter are required to prevent methylation of the CpG island. Genes Dev. 1994;8(19):2282–92.https://doi.org/10.1101/gad.8.19.2282
  5. Brandeis M, Frank D, Keshet I, Siegfried Z, Mendelsohn M, Nemes A, et al. Sp1 elements protect a CpG island from de novo methylation. Nature. 1994;371(6496):435–8.https://doi.org/10.1038/371435a0
  6. Lienert F, Wirbelauer C, Som I, Dean A, Mohn F, Schübeler D. Identification of genetic elements that autonomously determine DNA methylation states. Nat Genet. 2011;43(11):1091–7.https://doi.org/10.1038/ng.946
  7. Stadler MB, Murr R, Burger L, Ivanek R, Lienert F, Schöler A, et al. DNA-binding factors shape the mouse methylome at distal regulatory regions. Nature. 2011;480(7378):490–5.
  8. Ooi SK, Qiu C, Bernstein E, Li K, Jia D, Yang Z, et al. DNMT3L connects unmethylated lysine 4 of histone H3 to de novo methylation of DNA. Nature. 2007;448(7154):714–7.https://doi.org/10.1038/nature05987
  9. Wachter E, Quante T, Merusi C, Arczewska A, Stewart F, Webb S, et al. Synthetic CpG islands reveal DNA sequence determinants of chromatin structure. eLife. 2014;3:e03397.https://doi.org/10.7554/eLife.03397
  10. Illingworth RS, Gruenewald-Schneider U, De Sousa D, Webb S, Merusi C, Kerr AR, et al. Inter-individual variability contrasts with regional homogeneity in the human brain DNA methylome. Nucleic Acids Res. 2015;43(2):732–44.https://doi.org/10.1093/nar/gku1305
  11. Hitchins MP. Constitutional epimutation as a mechanism for cancer causality and heritability? Nat Rev Cancer. 2015;15(10):625–34.https://doi.org/10.1038/nrc4001
  12. Jones PA, Issa JP, Baylin S. Targeting the cancer epigenome for therapy. Nat Rev Genet. 2016;17(10):630–41.https://doi.org/10.1038/nrg.2016.93
  13. Hill VK, Ricketts C, Bieche I, Vacher S, Gentle D, Lewis C, et al. Genome-wide DNA methylation profiling of CpG islands in breast cancer identifies novel genes associated with tumorigenicity. Cancer Res. 2011;71(8):2988–99.https://doi.org/10.1158/0008-5472.CAN-10-4026
  14. Quante T, Bird A. Do short, frequent DNA sequence motifs mould the epigenome? Nat Rev Mol Cell Biol. 2016;17(4):257–62.https://doi.org/10.1038/nrm.2015.31
  15. Bird A. DNA methylation patterns and epigenetic memory. Genes Dev. 2002;16(1):6–21.https://doi.org/10.1101/gad.947102
  16. Bird A. The dinucleotide CG as a genomic signalling module. J Mol Biol. 2011;409(1):47–53.https://doi.org/10.1016/j.jmb.2011.01.056
  17. Thomson JP, Skene PJ, Selfridge J, Clouaire T, Guy J, Webb S, et al. CpG islands influence chromatin structure via the CpG-binding protein Cfp1. Nature. 2010;464(7291):1082–6.https://doi.org/10.1038/nature08924
  18. Blackledge NP, Farcas AM, Kondo T, King HW, McGouran JF, Hanssen LL, et al. Variant PRC1 complex-dependent H2A ubiquitylation drives PRC2 recruitment and polycomb domain formation. Cell. 2014;157(6):1445–59.https://doi.org/10.1016/j.cell.2014.05.004
  19. Blackledge NP, Zhou JC, Tolstorukov MY, Farcas AM, Park PJ, Klose RJ. CpG islands recruit a histone H3 lysine 36 demethylase. Mol Cell. 2010;38(2):179–90.https://doi.org/10.1016/j.molcel.2010.04.009
  20. Farcas AM, Blackledge NP, Sudbery I, Long HK, McGouran JF, Rose NR, et al. KDM2B links the Polycomb Repressive Complex 1 (PRC1) to recognition of CpG islands. eLife. 2012;1:e00205.https://doi.org/10.7554/eLife.00205
  21. Wu X, Johansen JV, Helin K. Fbxl10/Kdm2b recruits polycomb repressive complex 1 to CpG islands and regulates H2A ubiquitylation. Mol Cell. 2013;49(6):1134–46.https://doi.org/10.1016/j.molcel.2013.01.016
  22. Lee JH, Voo KS, Skalnik DG. Identification and characterization of the DNA binding domain of CpG-binding protein. J Biol Chem. 2001;276(48):44669–76.https://doi.org/10.1074/jbc.M107179200
  23. Bostick M, Kim JK, Estève PO, Clark A, Pradhan S, Jacobsen SE. UHRF1 plays a role in maintaining DNA methylation in mammalian cells. Science. 2007;317(5845):1760–4.https://doi.org/10.1126/science.1147939
  24. Hendrich B, Bird A. Identification and characterization of a family of mammalian methyl-CpG binding proteins. Mol Cell Biol. 1998;18(11):6538–47.https://doi.org/10.1128/MCB.18.11.6538
  25. Baubec T, Ivánek R, Lienert F, Schübeler D. Methylation-dependent and -independent genomic targeting principles of the MBD protein family. Cell. 2013;153(2):480–92.https://doi.org/10.1016/j.cell.2013.03.011
  26. Nan X, Campoy FJ, Bird A. MeCP2 is a transcriptional repressor with abundant binding sites in genomic chromatin. Cell. 1997;88(4):471–81.https://doi.org/10.1016/S0092-8674(00)81887-5
  27. Lee JH, Skalnik DG. CpG-binding protein (CXXC finger protein 1) is a component of the mammalian Set1 histone H3-Lys4 methyltransferase complex, the analogue of the yeast Set1/COMPASS complex. J Biol Chem. 2005;280(50):41725–31.https://doi.org/10.1074/jbc.M508312200
  28. Clouaire T, Webb S, Skene P, Illingworth R, Kerr A, Andrews R, et al. Cfp1 integrates both CpG content and gene activity for accurate H3K4me3 deposition in embryonic stem cells. Genes Dev. 2012;26(15):1714–28.https://doi.org/10.1101/gad.194209.112
  29. Lyst MJ, Ekiert R, Ebert DH, Merusi C, Nowak J, Selfridge J, et al. Rett syndrome mutations abolish the interaction of MeCP2 with the NCoR/SMRT co-repressor. Nat Neurosci. 2013;16(7):898–902.https://doi.org/10.1038/nn.3434
  30. Nan X, Ng HH, Johnson CA, Laherty CD, Turner BM, Eisenman RN, et al. Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex. Nature. 1998;393(6683):386–9.https://doi.org/10.1038/30764
  31. Wade PA, Gegonne A, Jones PL, Ballestar E, Aubry F, Wolffe AP. Mi-2 complex couples DNA methylation to chromatin remodelling and histone deacetylation. Nat Genet. 1999;23(1):62–6.https://doi.org/10.1038/12664
  32. Zhang Y, Ng H-H, Erdjument-Bromage H, Tempst P, Bird A, Reinberg D. Analysis of the NuRD subunits reveals a histone deacetylase core complex and a connection with DNA methylation. Genes Dev. 1999;13(15):1924–35.https://doi.org/10.1101/gad.13.15.1924
  33. Cohen NM, Kenigsberg E, Tanay A. Primate CpG islands are maintained by heterogeneous evolutionary regimes involving minimal selection. Cell. 2011;145(5):773–86.https://doi.org/10.1016/j.cell.2011.04.024
  34. Straussman R, Nejman D, Roberts D, Steinfeld I, Blum B, Benvenisty N, et al. Developmental programming of CpG island methylation profiles in the human genome. Nat Struct Mol Biol. 2009;16(5):564–71.https://doi.org/10.1038/nsmb.1594
  35. Lynch MD, Smith AJ, De Gobbi M, Flenley M, Hughes JR, Vernimmen D, et al. An interspecies analysis reveals a key role for unmethylated CpG dinucleotides in vertebrate Polycomb complex recruitment. EMBO J. 2012;31(2):317–29.https://doi.org/10.1038/emboj.2011.399
  36. Mendenhall EM, Koche RP, Truong T, Zhou VW, Issac B, Chi AS, et al. GC-rich sequence elements recruit PRC2 in mammalian ES cells. PLoS Genet. 2010;6(12):e1001244.https://doi.org/10.1371/journal.pgen.1001244
  37. Aravind L, Landsman D. AT-hook motifs identified in a wide variety of DNA-binding proteins. Nucleic Acids Res. 1998;26(19):4413–21.https://doi.org/10.1093/nar/26.19.4413
  38. Bernardi G, Olofsson B, Filipski J, Zerial M, Salinas J, Cuny G, et al. The mosaic genome of warm-blooded vertebrates. Science. 1985;228(4702):953–8.https://doi.org/10.1126/science.4001930
  39. Bernardi G. The isochore organization of the human genome. Annu Rev Genet. 1989;23(1):637–61.https://doi.org/10.1146/annurev.ge.23.120189.003225
  40. Holmquist GP. Chromosome bands, their chromatin flavors, and their functional features. Am J Hum Genet. 1992;51(1):17–37.
  41. Nora EP, Dekker J, Heard E. Segmental folding of chromosomes: a basis for structural and regulatory chromosomal neighborhoods? BioEssays. 2013;35(9):818–28.https://doi.org/10.1002/bies.201300040
  42. Bickmore WA, van Steensel B. Genome architecture: domain organization of interphase chromosomes. Cell. 2013;152(6):1270–84.https://doi.org/10.1016/j.cell.2013.02.001
  43. Wolfe KH, Sharp PM, Li W-H. Mutation rates differ among regions of the mammalian genome. Nature. 1989;337(6204):283–5.https://doi.org/10.1038/337283a0