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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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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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