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Genome-wide DNA replication profile for Drosophila melanogaster: a link between transcription and replication timing

Nature Genetics volume 32, pages 438–442 (2002)Cite this article

Abstract

Replication of the genome before mitotic cell division is a highly regulated process that ensures the fidelity of DNA duplication. DNA replication initiates at specific locations, termed origins of replication, and progresses in a defined temporal order during the S phase of the cell cycle. The relationship between replication timing and gene expression has been the subject of some speculation1. A recent genome-wide analysis in Saccharomyces cerevisiae showed no association between replication timing and gene expression2. In higher eukaryotes, the limited number of genomic loci analyzed has not permitted a firm conclusion regarding this association. To explore the relationship between DNA replication and gene expression in higher eukaryotes, we developed a strategy to measure the timing of DNA replication for thousands of genes in a single DNA array hybridization experiment. Using this approach, we generated a genome-wide map of replication timing for Drosophila melanogaster. Moreover, by surveying over 40% of all D. melanogaster genes, we found a strong correlation between DNA replication early in S phase and transcriptional activity. As this correlation does not exist in S. cerevisiae, this interplay between DNA replication and transcription may be a unique characteristic of higher eukaryotes.

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Figure 1: Experimental strategy to measure the timing of DNA replication using spotted microarrays.
Figure 2: Replication timing of genes in the part of chromosome 2L proximal to the telomere.
Figure 3: Replication profile for the sequenced D. melanogaster genome.
Figure 4: Relationship between transcription and timing of DNA replication.

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References

  1. Cimbora, D.M. & Groudine, M. The control of mammalian DNA replication: a brief history of space and timing. Cell 104, 643–646 (2001).

    CAS  PubMed  Google Scholar 

  2. Raghuraman, M.K. et al. Replication dynamics of the yeast genome. Science 294, 115–121 (2001).

    Article  CAS  Google Scholar 

  3. Ahmad, K. & Henikoff, S. Centromeres are specialized replication domains in heterochromatin. J. Cell. Biol. 153, 101–110 (2001).

    Article  CAS  Google Scholar 

  4. Dolfini, S., Courgeon, A.M. & Tiepolo, L. The cell cycle of an established line of Drosophila melanogaster cells in vitro. Experientia 26, 1020–1021 (1970).

    Article  CAS  Google Scholar 

  5. Hansen, R.S., Canfield, T.K., Lamb, M.M., Gartler, S.M. & Laird, C.D. Association of fragile X syndrome with delayed replication of the FMR1 gene. Cell 73, 1403–1409 (1993).

    Article  CAS  Google Scholar 

  6. Rubin, G.M. et al. A Drosophila complementary DNA resource. Science 287, 2222–2224 (2000).

    Article  CAS  Google Scholar 

  7. Cleveland, W.S. & Devlin, S.J. Locally-weighted regression: an approach to regression analysis by local fitting. J. Amer. Statist. Assoc. 83, 596–610 (1988).

    Article  Google Scholar 

  8. Gilbert, D.M. Replication timing and transcriptional control: beyond cause and effect. Curr. Opin. Cell Biol. 14, 377–383 (2002).

    Article  CAS  Google Scholar 

  9. Sullivan, B. & Karpen, G. Centromere identity in Drosophila is not determined in vivo by replication timing. J. Cell. Biol. 154, 683–690 (2001).

    Article  CAS  Google Scholar 

  10. Caizzi, R., Caggese, C. & Pimpinelli, S. Bari-1, a new transposon-like family in Drosophila melanogaster with a unique heterochromatic organization. Genetics 133, 335–345 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Jakubczak, J.L., Zenni, M.K., Woodruff, R.C. & Eickbush, T.H. Turnover of R1 (type I) and R2 (type II) retrotransposable elements in the ribosomal DNA of Drosophila melanogaster. Genetics 131, 129–142 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Wakimoto, B.T. & Hearn, M.G. The effects of chromosome rearrangements on the expression of heterochromatic genes in chromosome 2L of Drosophila melanogaster. Genetics 125, 141–154 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Eberl, D.F., Duyf, B.J. & Hilliker, A.J. The role of heterochromatin in the expression of a heterochromatic gene, the rolled locus of Drosophila melanogaster. Genetics 134, 277–292 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Hatton, K.S. et al. Replication program of active and inactive multigene families in mammalian cells. Mol. Cell. Biol. 8, 2149–2158 (1988).

    Article  CAS  Google Scholar 

  15. Cimbora, D.M. et al. Long-distance control of origin choice and replication timing in the human β-globin locus are independent of the locus control region. Mol. Cell. Biol. 20, 5581–5591 (2000).

    Article  CAS  Google Scholar 

  16. Hansen, R.S., Canfield, T.K. & Gartler, S.M. Reverse replication timing for the XIST gene in human fibroblasts. Hum. Mol. Genet. 4, 813–820 (1995).

    Article  CAS  Google Scholar 

  17. Smith, Z.E. & Higgs, D.R. The pattern of replication at a human telomeric region (16p13.3): its relationship to chromosome structure and gene expression. Hum. Mol. Genet. 8, 1373–1386 (1999).

    Article  CAS  Google Scholar 

  18. Kennedy, B.K., Barbie, D.A., Classon, M., Dyson, N. & Harlow, E. Nuclear organization of DNA replication in primary mammalian cells. Genes. Dev. 14, 2855–2868 (2000).

    Article  CAS  Google Scholar 

  19. DePamphilis, M.L. Replication origins in metazoan chromosomes: fact or fiction? Bioessays 21, 5–16 (1999).

    Article  CAS  Google Scholar 

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

    Article  CAS  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  Google Scholar 

  22. Kooperberg, C., Fazzio, T.G., Delrow, J. & Tsukiyama, T. Improved background correction for spotted DNA microarrays. J. Comput. Biol. 9, 55–66 (2002).

    Article  CAS  Google Scholar 

  23. Yang, Y.H., Dudoit, S., Luu, P. & Speed, T.P. Normalization for cDNA microarrays data. in Microarrays: Optical Technologies and Informatics (eds Bittner, M.L., Chen, Y., Dorsel, A.N. and Dougherty, E.R.) (International Society for Optical Engineering, San Jose, California, 2001).

    Google Scholar 

  24. Pritchard, C.C., Hsu, L., Delrow, J. & Nelson, P.S. Project normal: defining normal variance in mouse gene expression. Proc. Natl Acad. Sci. USA 98, 13266–13271 (2001).

    Article  CAS  Google Scholar 

  25. Fan, J. & Gijbels, I. Local Polynomial Modelling and its Applications (Chapman-Hall, London, 1996).

    Google Scholar 

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Acknowledgements

We thank A. Oryan for Kc cells; E. Giniger for coordinating the assembly of the Northwest Fly Consortium microarray; C. Neal for array construction and cDNA analysis; J. Schreiber, D. Cimbora and members of the Groudine lab for suggestions; and S. Henikoff, D. Gottschling and M. Lorincz for comments on the manuscript. This work was supported in part by US National Institute of Health grants to M.G. and C.K., a grant from the Netherlands Academy of Sciences to B.v.S. and a fellowship grant from the Rett Syndrome Research Foundation to D.S.

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Authors and Affiliations

  1. Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, 98109, Washington, USA

    Dirk Schübeler, David Scalzo & Mark Groudine

  2. Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, 98109, Washington, USA

    Charles Kooperberg

  3. Netherlands Cancer Institute, Amsterdam, The Netherlands

    Bas van Steensel

  4. DNA array facility, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA

    Jeffrey Delrow

  5. Department of Radiation Oncology, University of Washington, Seattle, Washington, USA

    Mark Groudine

Authors
  1. Dirk Schübeler
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  6. Mark Groudine
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Correspondence to Dirk Schübeler or Mark Groudine.

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Schübeler, D., Scalzo, D., Kooperberg, C. et al. Genome-wide DNA replication profile for Drosophila melanogaster: a link between transcription and replication timing. Nat Genet 32, 438–442 (2002). https://doi.org/10.1038/ng1005

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