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.

Nucleosome dynamics define transcriptional enhancers

Nature Genetics volume 42, pages 343–347 (2010)Cite this article

Subjects

Abstract

Chromatin plays a central role in eukaryotic gene regulation. We performed genome-wide mapping of epigenetically marked nucleosomes to determine their position both near transcription start sites and at distal regulatory elements, including enhancers. In prostate cancer cells, where androgen receptor binds primarily to enhancers, we found that androgen treatment dismisses a central nucleosome present at androgen receptor binding sites that is flanked by a pair of marked nucleosomes. A new quantitative model built on the behavior of such nucleosome pairs correctly identified regions bound by the regulators of the immediate androgen response, including androgen receptor and FOXA1. More importantly, this model also correctly predicted previously unidentified binding sites for other transcription factors present after prolonged androgen stimulation, including OCT1 and NKX3-1. Therefore, quantitative modeling of enhancer structure provides a powerful predictive method to infer the identity of transcription factors involved in cellular responses to specific stimuli.

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

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

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

Figure 1: Signal distribution and nucleosome position analysis in the androgen receptor and FOXA1 binding regions identified by ChIP-chip experiments and the TSS.
Figure 2: qPCR validation of the nucleosomes stabilized-destabilized around androgen receptor (AR) binding sites.
Figure 3: Motif analysis in the paired nucleosome regions.
Figure 4: ChIP-qPCR and gene expression analysis of NSD scoring sites.

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  1. Beato, M. & Eisfeld, K. Transcription factor access to chromatin. Nucleic Acids Res. 25, 3559–3563 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Narlikar, L., Gordan, R. & Hartemink, A.J. A nucleosome-guided map of transcription factor binding sites in yeast. PLOS Comput. Biol. 3, e215 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  3. Ozsolak, F. et al. Chromatin structure analyses identify miRNA promoters. Genes Dev. 22, 3172–3183 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Guttman, M. et al. Chromatin signature reveals over a thousand highly conserved large non-coding RNAs in mammals. Nature 458, 223–227 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Yuan, G.C. et al. Genome-scale identification of nucleosome positions in S. cerevisiae. Science 309, 626–630 (2005).

    Article  CAS  PubMed  Google Scholar 

  6. Lee, W. et al. A high-resolution atlas of nucleosome occupancy in yeast. Nat. Genet. 39, 1235–1244 (2007).

    Article  CAS  PubMed  Google Scholar 

  7. Mavrich, T.N. et al. A barrier nucleosome model for statistical positioning of nucleosomes throughout the yeast genome. Genome Res. 18, 1073–1083 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Mavrich, T.N. et al. Nucleosome organization in the Drosophila genome. Nature 453, 358–362 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Valouev, A. et al. A high-resolution, nucleosome position map of C. elegans reveals a lack of universal sequence-dictated positioning. Genome Res. 18, 1051–1063 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Ozsolak, F., Song, J.S., Liu, X.S. & Fisher, D.E. High-throughput mapping of the chromatin structure of human promoters. Nat. Biotechnol. 25, 244–248 (2007).

    Article  CAS  PubMed  Google Scholar 

  11. Schones, D.E. et al. Dynamic regulation of nucleosome positioning in the human genome. Cell 132, 887–898 (2008).

    Article  CAS  PubMed  Google Scholar 

  12. Blackwood, E.M. & Kadonaga, J.T. Going the distance: a current view of enhancer action. Science 281, 60–63 (1998).

    Article  CAS  PubMed  Google Scholar 

  13. Bulger, M. & Groudine, M. Looping versus linking: toward a model for long-distance gene activation. Genes Dev. 13, 2465–2477 (1999).

    Article  CAS  PubMed  Google Scholar 

  14. Barski, A. et al. High-resolution profiling of histone methylations in the human genome. Cell 129, 823–837 (2007).

    Article  CAS  PubMed  Google Scholar 

  15. Heintzman, N.D. et al. Distinct and predictive chromatin signatures of transcriptional promoters and enhancers in the human genome. Nat. Genet. 39, 311–318 (2007).

    Article  CAS  PubMed  Google Scholar 

  16. Lupien, M. et al. FoxA1 translates epigenetic signatures into enhancer-driven lineage-specific transcription. Cell 132, 958–970 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Zhang, Y., Shin, H., Song, J.S., Lei, Y. & Liu, X.S. Identifying positioned nucleosomes with epigenetic marks in human from ChIP-Seq. BMC Genomics 9, 537 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  18. Peckham, H.E. et al. Nucleosome positioning signals in genomic DNA. Genome Res. 17, 1170–1177 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Yuan, G.C. & Liu, J.S. Genomic sequence is highly predictive of local nucleosome depletion. PLOS Comput. Biol. 4, e13 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  20. Kornberg, R.D. & Stryer, L. Statistical distributions of nucleosomes: nonrandom locations by a stochastic mechanism. Nucleic Acids Res. 16, 6677–6690 (1988).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Jin, C. et al. H3.3/H2A.Z double variant-containing nucleosomes mark 'nucleosome-free regions' of active promoters and other regulatory regions. Nat. Genet. 41, 941–945 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Korkmaz, C.G. et al. Analysis of androgen regulated homeobox gene NKX3.1 during prostate carcinogenesis. J. Urol. 172, 1134–1139 (2004).

    Article  CAS  PubMed  Google Scholar 

  23. Asatiani, E. et al. Deletion, methylation, and expression of the NKX3.1 suppressor gene in primary human prostate cancer. Cancer Res. 65, 1164–1173 (2005).

    Article  CAS  PubMed  Google Scholar 

  24. Wang, Q. et al. A hierarchical network of transcription factors governs androgen receptor-dependent prostate cancer growth. Mol. Cell 27, 380–392 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  25. Wang, Q. et al. Androgen receptor regulates a distinct transcription program in androgen-independent prostate cancer. Cell 138, 245–256 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Liu, W. et al. Characterization of two functional NKX3.1 binding sites upstream of the PCAN1 gene that are involved in the positive regulation of PCAN1 gene transcription. BMC Mol. Biol. 9, 45 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  27. Wang, Q., Carroll, J.S. & Brown, M. Spatial and temporal recruitment of androgen receptor and its coactivators involves chromosomal looping and polymerase tracking. Mol. Cell 19, 631–642 (2005).

    Article  CAS  PubMed  Google Scholar 

  28. Zhang, Y. et al. Model-based analysis of ChIP-Seq (MACS). Genome Biol. 9, R137 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  29. Matys, V. et al. TRANSFAC and its module TRANSCompel: transcriptional gene regulation in eukaryotes. Nucleic Acids Res. 34, D108–D110 (2006).

    Article  CAS  PubMed  Google Scholar 

  30. Irizarry, R.A. et al. Exploration, normalization, and summaries of high density oligonucleotide array probe level data. Biostatistics 4, 249–264 (2003).

    Article  PubMed  Google Scholar 

  31. Dai, M. et al. Evolving gene/transcript definitions significantly alter the interpretation of GeneChip data. Nucleic Acids Res. 33, e175 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  32. Tusher, V.G., Tibshirani, R. & Chu, G. Significance analysis of microarrays applied to the ionizing radiation response. Proc. Natl. Acad. Sci. USA 98, 5116–5121 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from US National Institutes of Health (1R01 HG004069-02 to X.S.L., and 2P50 CA090381-06 to X.S.L. and M.B.), the Department of Defense (W81XWH-07-1-0037 to X.S.L.) and the Prostate Cancer Foundation (to M.B.).

Author information

Author notes

  1. Qianben Wang, Yong Zhang & Mathieu Lupien

    Present address: Present addresses: Department of Molecular and Cellular Biochemistry and the Comprehensive Cancer Center, Ohio State University College of Medicine, Columbus, Ohio, USA (Q.W.); School of Life Science and Technology, Tongji University, Shanghai, China (Y.Z.); and Department of Genetics, Norris Cotton Cancer Center, Dartmouth Medical School, Lebanon, New Hampshire, USA (M.L.).,

  2. Housheng Hansen He and Clifford A Meyer: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Harvard School of Public Health, Boston, Massachusetts, USA

    Housheng Hansen He, Clifford A Meyer, Hyunjin Shin, Yong Zhang & X Shirley Liu

  2. Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA

    Housheng Hansen He, Shannon T Bailey, Qianben Wang, Kexin Xu, Min Ni, Mathieu Lupien & Myles Brown

  3. Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA

    Gang Wei & Keji Zhao

  4. Department of Biology, Carolina Center for the Genome Sciences and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, USA

    Piotr Mieczkowski & Jason D Lieb

Authors
  1. Housheng Hansen He
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Clifford A Meyer
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hyunjin Shin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Shannon T Bailey
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Gang Wei
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Qianben Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yong Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Kexin Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Min Ni
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Mathieu Lupien
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Piotr Mieczkowski
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Jason D Lieb
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Keji Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Myles Brown
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. X Shirley Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

H.H.H., C.A.M., K.Z., J.D.L., X.S.L. and M.B. designed the experiments. H.H.H., S.T.B., G.W., Q.W., K.X., M.N., M.L. and P.M. performed the experiments. C.A.M., H.H.H., H.S. and Y.Z. performed data analysis. C.A.M., H.H.H., X.S.L., M.B., J.D.L. and M.L. wrote the manuscript.

Corresponding authors

Correspondence to Myles Brown or X Shirley Liu.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–7 and Supplementary Tables 1–3 (PDF 1000 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

He, H., Meyer, C., Shin, H. et al. Nucleosome dynamics define transcriptional enhancers. Nat Genet 42, 343–347 (2010). https://doi.org/10.1038/ng.545

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng.545

This article is cited by

Search

Advanced 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