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Nucleosome dynamics define transcriptional enhancers

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.

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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.

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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 

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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.).

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Authors and Affiliations

Authors

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.

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The authors declare no competing financial interests.

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

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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

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