Evolution of CpG-islands by means of tandem duplications

CG-rich islands (CpG-islands, or CGI) are important functional elements in a genome of vertebrates. In particular, they: a) initiate transcription as promoters in most (> 50 %) genes of vertebrates, in some cases bi-directional, due to self-complement feature of cg dinucleotides; b) form a global methylation landscape; c) act as a transcription “switch” via methylation. The degenerate nature of CpG-island (elevated CG composition) implies an increase in the probability of tandem repeats and palindromes within CpG- island. This work is devoted to the identification of tandem duplications of complete CpG-islands, i. e. considering mega monomers of size 400–5 000 bp, in the human genome. We found a range of inter- and intragenic tandem duplications of CpG-islands. Intergenic CpGi duplication mediates through CG-rich telomeric satellites, as well as elements of the SINE. One of the most pronounced tandems are located in chromosome 19, known for its abundance of segment duplications and gene expansion. We also underline the unique genomic segment, which is DXZ4 mega satellite, in q arm of chromosome X, also falling into the category of CpG-islands which evolved by tandem duplications rounds.

1. Anderson S.K. Probabilistic bidirectional promoter switches: noncoding RNA takes control. Mol. Ther. Nucl. Acids. 2014;3:e191.

2. Babenko V.N., Kosarev P.S., Vishnevsky O.V., Levitsky V.G., Basin V.V., Frolov A.S. Investigating extended regulatory regions of genomic DNA sequences. Bioinformatics. 1999;15(7-8):644-653.

3. Branciamore S., Chen Z.X., Riggs A.D., Rodin S.N. CpG island clusters and pro-epigenetic selection for CpGs in protein-coding exons of HOX and other transcription factors. Proc. Natl. Acad. Sci. USA. 2010;107(35):15485-15490.

4. Chadwick B.P. DXZ4 chromatin adopts an opposing conformation to that of the surrounding chromosome and acquires a novel inactive X-specific role involving CTCF and antisense transcripts. Gen. Res. 2008;18:1259-1269. DOI 10.1101/gr.075713.107.

5. Darrow E.M., Chadwick B.P. A novel tRNA variable number tandem repeat at human chromosome 1q23.3 is implicated as a boundary element based on conservation of a CTCF motif in mouse. Nucl. Acids Res. 2014;42(10):6421-6435.

6. Das S., Chadwick B.P. Influence of repressive histone and DNA methylation upon D4Z4 transcription in non-myogenic cells. PLoS One. 2016;11(7):e0160022.DOI 10.1371/journal.pone.0160022.

7. Deaton A.M., Bird A. CpG islands and the regulation of transcription. Gen. Dev. 2011;25(10):1010-1022.

8. Epstein N.D., Karlsson S., O’Brien S., Modi W., Moulton A., Nienhuis A.W. A new moderately repetitive DNA sequence family of novel organization. Nucl. Acids Res. 1987;15:2327-2341.

9. Fenouil R., Cauchy P., Koch F., Descostes N., Cabeza J.Z., Innocenti C., Ferrier P., Spicuglia S., Gut M., Gut I., Andrau J.C. CpG islands and GC content dictate nucleosome depletion in a transcription- independent manner at mammalian promoters. Genome Res. 2012;22(12):2399-2408.

10. Gardiner-Garden M., Frommer M. CpG islands in vertebrate genomes. J. Mol. Biol. 1987;196:261-282.

11. Giacalone J., Friedes J., Francke U. A novel GC-rich human macrosatellite VNTR in Xq24 is differentially methylated on active and inactive X chromosomes. Nat. Genet. 1992;1(2):137-43.

12. Giannakakis A., Zhang J., Jenjaroenpun P., Nama S., Zainolabidin N., Aau M.Y., Yarmishyn A.A., Vaz C., Ivshina A.V., Grinchuk O.V., Voorhoeve M., Vardy L.A., Sampath P., Kuznetsov V.A., Kurochkin I.V., Guccione E. Contrasting expression patterns of coding and noncoding parts of the human genome upon oxidative stress. Sci. Rep. 2015;5:9737. DOI 10.1038/srep09737.

13. Grandi F.C., Rosser J.M., Newkirk S.J., Yin J., Jiang X., Xing Z., Whitmore L., Bashir S., Ivics Z., Izsvák Z., Ye P., Yu Y.E., An W. Retrotransposition creates sloping shores: a graded influence of hypomethylated CpG islands on flanking CpG sites. Genome Res. 2015; 25(8):1135-1146.

14. Grimwood J., Gordon L.A., Olsen A., Terry A., Schmutz J., Lamerdin J., … Stubbs L., Rokhsar D.S., Myers R.M., Rubin E.M., Lucas S.M. The DNA sequence and biology of human chromosome 19. Nature. 2004;428(6982):529-535.

15. Guo Y., Xu Q., Canzio D., Shou J., Li J., Gorkin D.U., Jung I., Wu H., Zhai Y., Tang Y., Lu Y., Wu Y., Jia Z., Li W., Zhang M.Q., Ren B., Krainer A.R., Maniatis T., Wu Q. CRISPR inversion of CTCF sites alters genome topology and enhancer/promoter function. Cell. 2015; 162(4):900-910. DOI 10.1016/j.cell.2015.07.038.

16. Haerter J.O., Lövkvist C., Dodd I.B., Sneppen K. Collaboration between CpG sites is needed for stable somatic inheritance of DNA methylation states. Nucl. Acids Res. 2014;42(4):2235-2244.

17. Hewitt J.E., Lyle R., Clark L.N., Valleley E.M., Wright T.J., Wijmenga C., van Deutekom J.C.T., Francis F., Sharpe P.T., Hofker M., Frants R.R., Williamson R. Analysis of the tandem repeat locus D4Z4 associated with facioscapulohumeral muscular dystrophy. Hum. Mol. Genet. 1994;3(8):1287-1295. DOI 10.1093/hmg/3.8.1287.

18. Horakova A.H., Moseley S.C., McLaughlin C.R., Tremblay D.C., Chadwick B.P. The macrosatellite DXZ4 mediates CTCF-dependent long-range intrachromosomal interactions on the human inactive X chromosome. Hum. Mol. Genet. 2012;21(20):4367-4377.

19. Illingworth R.S., Bird A.P. CpG islands – ‘a rough guide’. FEBS Lett. 2009;583(11):1713-20. DOI 10.1016/j.febslet.2009.04.012.

20. Kang J.Y., Song S.H., Yun J., Jeon M.S., Kim H.P., Han S.W., Kim T.Y. Disruption of CTCF/cohesin-mediated high-order chromatin structures by DNA methylation downregulates PTGS2 expression. Oncogene. 2015;34:5677-5684. DOI 10.1038/onc.2015.17.

21. Lukic S., Nicolas J.C., Levine A.J. The diversity of zinc-finger genes on human chromosome 19 provides an evolutionary mechanism for defense against inherited endogenous retroviruses. Cell Death Differ. 2014;21(3):381-387. DOI 10.1038/cdd.2013.150.

22. Nichols M.H., Corces V.G. A CTCF code for 3D genome architecture. Cell. 2015;162(4):703-705. DOI 10.1016/j.cell.2015.07.053.

23. Ong C.T., Corces V.G. CTCF: an architectural protein bridging genome topology and function. Nat. Rev. Genet. 2014;15(4):234-246.

24. Ottaviani A., Schluth-Bolard C., Gilson E., Magdinier F. D4Z4 as a prototype of CTCF and lamins-dependent insulator in human cells. Nucleus. 2010;1(1):30-36.

25. Qu Y., Lennartsson A., Gaidzik V.I., Deneberg S., Karimi M., Bengtzén S., Höglund M., Bullinger L., Döhner K., Lehmann S. Differential methylation in CN-AML preferentially targets non-CGI regions and is dictated by DNMT3A mutational status and associated with predominant hypomethylation of HOX genes. Epigenetics. 2014; 9(8):1108-1119.

26. Rao S.S., Huntley M.H., Durand N.C., Stamenova E.K., Bochkov I.D., Robinson J.T., Sanborn A.L., Machol I., Omer A.D., Lander E.S., Aiden E.L. A 3D map of the human genome at kilobase resolution reveals principles of chromatin looping. Cell. 2014;159(7):1665- 1680.

27. Sandoval J., Heyn H., Moran S., Serra-Musach J., Pujana M.A., Bibikova M., Esteller M. Validation of a DNA methylation microarray for 450,000 CpG sites in the human genome. Epigenetics. 2011; 6(6):692-702.

28. Schaap M., Lemmers R.J., Maassen R., van der Vliet P.J., Hoogerheide L.F., van Dijk H.K., Baştürk N., de Knijff P., van der Maarel S.M. Genome-wide analysis of macrosatellite repeat copy number variation in worldwide populations: evidence for differences and commonalities in size distributions and size restrictions. BMC Genomics. 2013;4(14):143. DOI 10.1186/1471-2164-14-143.

29. Smit A.F.A., Hubley R. RepeatModeler Open-1.0. 2008–2015. http://www.repeatmasker.org.

30. Sohn B.H., Park I.Y., Lee J.J., Yang S.J., Jang Y.J., Park K.C., Kim D.J., Lee D.C., Sohn H.A., Kim T.W., Yoo H.S., Choi J.Y., Bae Y.S., Yeom Y.I. Functional switching of transforming growth factor-beta1 signaling in liver cancer via epigenetic modulation of a single CpG site in tristetraprolin promoter. Gastroenterol. 2010;138:1898-1908.

31. Thijssen P.E., Balog J., Yao Z., Pham T.P., Tawil R., Tapscott S.J., van der Maarel S.M. DUX4 promotes transcription of FRG2 by directly activating its promoter in facioscapulohumeral muscular dystrophy. Skeletal Muscle. 2014;4:19. DOI 10.1186/2044-5040-4-19.

32. Treangen T.J., Salzberg S.L. Repetitive DNA and next-generation sequencing: computational challenges and solutions. Nat. Rev. Genet. 2012;13:36-46.

33. Tremblay D.C., Alexander G., Jr., Moseley S., Chadwick B.P. Expression, tandem repeat copy number variation and stability of four macrosatellite arrays in the human genome. BMC Genomics. 2010;15(11):632. DOI 10.1186/1471-2164-11-632.

34. Vavouri T., Lehner B. Human genes with CpG island promoters have a distinct transcription- associated chromatin organization. Genome Biol. 2012;13(11):R110.

35. Vinogradov A.E. Noncoding DNA, isochores and gene expression: nucleosome formation potential. Nucl. Acids Res. 2005;33(2):559-563.

36. Wang H., Maurano M.T., Qu H., Varley K.E., Gertz J., Pauli F., Lee K., Canfield T., Weaver M., Sandstrom R., Thurman R.E., Kaul R., Myers R.M., Stamatoyannopoulos J.A. Widespread plasticity in CTCF occupancy linked to DNA methylation. Gen. Res. 2012;22(9):1680-1688.

37. Warburton P.E., Hasson D., Guillem F., Lescale C., Jin X., Abrusan G. Analysis of the largest tandemly repeated DNA families in the human genome. BMC Genomics. 2008;9:533. DOI 10.1186/1471-2164-9-533.

38. Williams Z., Morozov P., Mihailovic A., Lin C., Puvvula P.K., Juranek S., Rosenwaks Z., Tuschl T. Discovery and characterization of piRNAs in the human fetal ovary. Cell Rep. 2015;13(4):854-863.

39. Wood E.J., Chin-Inmanu K., Jia H., Lipovich L. Sense-antisense gene pairs: sequence, transcription, and structure are not conserved between human and mouse. Front. Genet. 2013;4:183.

40. Zhang Y.Z., Sun S.C., Wu H.C., Fan Q.S., Song Y.J., Yu W., Jeanpierre M., Urtizberea J.A. Polymorphism of the D4Z4 locus associated with facioscapulohumeral muscular dystrophy 1A in Shanghai population. Zhonghua Yi Xue Yi Chuan Xue Za Zhi (=Chinese J. Med. Genetics). 2005;22(4):380-382.