Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Evidence for nucleosome depletion at active regulatory regions genome-wide

Abstract

The identification of nuclease-hypersensitive sites in an active globin gene1 and in the 5′ regions of fruit fly heat shock genes2 first suggested that chromatin changes accompany gene regulation in vivo. Here we present evidence that the basic repeating units of eukaryotic chromatin, nucleosomes, are depleted from active regulatory elements throughout the Saccharomyces cerevisiae genome in vivo. We found that during rapid mitotic growth, the level of nucleosome occupancy is inversely proportional to the transcriptional initiation rate at the promoter. We also observed a partial loss of histone H3 and H4 tetramers from the coding regions of the most heavily transcribed genes. Alterations in the global transcriptional program caused by heat shock or a change in carbon source resulted in an increased nucleosome occupancy at repressed promoters, and a decreased nucleosome occupancy at promoters that became active. Nuclease-hypersensitive sites occur in species from yeast to humans and result from chromatin perturbation3,4,5. Given the conservation of sequence and function among components of both chromatin and the transcriptional machinery, nucleosome depletion at promoters may be a fundamental feature of eukaryotic transcriptional regulation.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Evidence for lower nucleosome occupancy in noncoding regions than in coding regions.
Figure 2: The inverse relationship between transcriptional activity and histones H3 and H4 occupancy.
Figure 3: Histone H3 ChIP assayed at GAL10 under transcriptionally inactive and active conditions.
Figure 4: Inverse relationship between transcriptional response and nucleosome occupancy upon heat shock.

Similar content being viewed by others

References

  1. Weintraub, H. & Groudine, M. Chromosomal subunits in active genes have an altered conformation. Science 193, 848–856 (1976).

    Article  CAS  Google Scholar 

  2. Wu, C., Wong, Y.C. & Elgin, S.C. The chromatin structure of specific genes: II. Disruption of chromatin structure during gene activity. Cell 16, 807–814 (1979).

    Article  CAS  Google Scholar 

  3. Elgin, S.C. DNAase I-hypersensitive sites of chromatin. Cell 27, 413–415 (1981).

    Article  CAS  Google Scholar 

  4. Reinke, H. & Horz, W. Histones are first hyperacetylated and then lose contact with the activated PHO5 promoter. Mol. Cell 11, 1599–1607 (2003).

    Article  CAS  Google Scholar 

  5. Boeger, H., Griesenbeck, J., Strattan, J.S. & Kornberg, R.D. Nucleosomes unfold completely at a transcriptionally active promoter. Mol. Cell 11, 1587–1598 (2003).

    Article  CAS  Google Scholar 

  6. Svaren, J. & Horz, W. Transcription factors vs nucleosomes: regulation of the PHO5 promoter in yeast. Trends Biochem. Sci. 22, 93–97 (1997).

    Article  CAS  Google Scholar 

  7. Boeger, H., Griesenbeck, J., Strattan, J.S. & Kornberg, R.D. Removal of promoter nucleosomes by disassembly rather than sliding in vivo. Mol. Cell 14, 667–673 (2004).

    Article  CAS  Google Scholar 

  8. Fedor, M.J. & Kornberg, R.D. Upstream activation sequence-dependent alteration of chromatin structure and transcription activation of the yeast GAL1-GAL10 genes. Mol. Cell. Biol. 9, 1721–1732 (1989).

    Article  CAS  Google Scholar 

  9. Lohr, D. Nucleosome transactions on the promoters of the yeast GAL and PHO genes. J. Biol. Chem. 272, 26795–26798 (1997).

    Article  CAS  Google Scholar 

  10. Dammann, R., Lucchini, R., Koller, T. & Sogo, J.M. Chromatin structures and transcription of rDNA in yeast Saccharomyces cerevisiae. Nucleic Acids Res. 21, 2331–2338 (1993).

    Article  CAS  Google Scholar 

  11. Holstege, F.C. et al. Dissecting the regulatory circuitry of a eukaryotic genome. Cell 95, 717–728 (1998).

    Article  CAS  Google Scholar 

  12. Belotserkovskaya, R. et al. FACT facilitates transcription-dependent nucleosome alteration. Science 301, 1090–1093 (2003).

    Article  CAS  Google Scholar 

  13. Cavalli, G. & Thoma, F. Chromatin transitions during activation and repression of galactose-regulated genes in yeast. EMBO J. 12, 4603–4613 (1993).

    Article  CAS  Google Scholar 

  14. Li, B., Nierras, C.R. & Warner, J.R. Transcriptional elements involved in the repression of ribosomal protein synthesis. Mol. Cell. Biol. 19, 5393–5404 (1999).

    Article  CAS  Google Scholar 

  15. Gasch, A.P. et al. Genomic expression programs in the response of yeast cells to environmental changes. Mol. Biol. Cell 11, 4241–4257 (2000).

    Article  CAS  Google Scholar 

  16. Causton, H.C. et al. Remodeling of yeast genome expression in response to environmental changes. Mol. Biol. Cell 12, 323–337 (2001).

    Article  CAS  Google Scholar 

  17. 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 

  18. Yu, L. & Morse, R.H. Chromatin opening and transactivator potentiation by RAP1 in Saccharomyces cerevisiae. Mol. Cell. Biol. 19, 5279–5288 (1999).

    Article  CAS  Google Scholar 

  19. Kuo, M.H., Zhou, J., Jambeck, P., Churchill, M.E. & Allis, C.D. Histone acetyltransferase activity of yeast Gcn5p is required for the activation of target genes in vivo. Genes Dev. 12, 627–639 (1998).

    Article  CAS  Google Scholar 

  20. Schnitzler, G., Sif, S. & Kingston, R.E. Human SWI/SNF interconverts a nucleosome between its base state and a stable remodeled state. Cell 94, 17–27 (1998).

    Article  CAS  Google Scholar 

  21. Lusser, A. & Kadonaga, J.T. Chromatin remodeling by ATP-dependent molecular machines. Bioessays 25, 1192–1200 (2003).

    Article  CAS  Google Scholar 

  22. Adkins, M.W., Howar, S.R. & Tyler, J.K. Chromatin disassembly mediated by the histone chaperone Asf1 is essential for transcriptional activation of the yeast PHO5 and PHO8 genes. Mol. Cell 14, 657–666 (2004).

    Article  CAS  Google Scholar 

  23. Nagy, P.L., Cleary, M.L., Brown, P.O. & Lieb, J.D. Genomewide demarcation of RNA polymerase II transcription units revealed by physical fractionation of chromatin. Proc. Natl. Acad. Sci. USA 100, 6364–6369 (2003).

    Article  CAS  Google Scholar 

  24. Li, S. & Smerdon, M.J. Nucleosome structure and repair of N-methylpurines in the GAL1-10 genes of Saccharomyces cerevisiae. J. Biol. Chem. 277, 44651–44659 (2002).

    Article  CAS  Google Scholar 

  25. Jackson, V. Formaldehyde cross-linking for studying nucleosomal dynamics. Methods 17, 125–139 (1999).

    Article  CAS  Google Scholar 

  26. Kuo, M.H. & Allis, C.D. In vivo cross-linking and immunoprecipitation for studying dynamic Protein:DNA associations in a chromatin environment. Methods 19, 425–433 (1999).

    Article  CAS  Google Scholar 

  27. Ng, H.H., Ciccone, D.N., Morshead, K.B., Oettinger, M.A. & Struhl, K. Lysine-79 of histone H3 is hypomethylated at silenced loci in yeast and mammalian cells: A potential mechanism for position-effect variegation. Proc. Natl. Acad. Sci. USA 100, 1820–1825 (2003).

    Article  CAS  Google Scholar 

  28. Liu, C.L., Schreiber, S.L. & Bernstein, B.E. Development and validation of a T7 based linear amplification for genomic DNA. BMC Genomics 4, 19 (2003).

    Article  CAS  Google Scholar 

  29. Yang, Y.H. et al. Normalization for cDNA microarray data: a robust composite method addressing single and multiple slide systematic variation. Nucleic Acids Res. 30, e15 (2002).

    Article  Google Scholar 

Download references

Acknowledgements

We thank T. Petes, T. Magnuson, W. Marzluff and S. Henikoff for comments on the manuscript and K. Struhl for yeast strains. This work was supported by a National Human Genome Research Institute grant to J.D.L. and a National Institute of General Medical Sciences grant to B.D.S. B.D.S. is a Pew Scholar in the Biomedical Sciences.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Jason D Lieb.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lee, CK., Shibata, Y., Rao, B. et al. Evidence for nucleosome depletion at active regulatory regions genome-wide. Nat Genet 36, 900–905 (2004). https://doi.org/10.1038/ng1400

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng1400

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing