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The nucleosome map of the mammalian liver

Nature Structural & Molecular Biology volume 18, pages 742–746 (2011)Cite this article

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Abstract

Binding to nucleosomal DNA is critical for 'pioneer' transcription factors such as the winged-helix transcription factors Foxa1 and Foxa2 to regulate chromatin structure and gene activation. Here we report the genome-wide map of nucleosome positions in the mouse liver, with emphasis on transcriptional start sites, CpG islands, Foxa2 binding sites and their correlation with gene expression. Despite the heterogeneity of liver tissue, we could clearly discern the nucleosome pattern of the predominant liver cell, the hepatocyte. By analyzing nucleosome occupancy and the distributions of heterochromatin protein 1 (Hp1), CBP (also known as Crebbp) and p300 (Ep300) in Foxa1- and Foxa2-deficient livers, we find that the maintenance of nucleosome position and chromatin structure surrounding Foxa2 binding sites is independent of Foxa1 and Foxa2.

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Figure 1: Mapping of nucleosome positions by micrococcal nuclease is more informative than the use of H3K4me1 ChIP-Seq data.
Figure 2: Nucleosome dynamics in the mouse liver.
Figure 3: Genome-wide distributions of Foxa2 and nucleosomes in the adult mouse liver.
Figure 4: The maintenance of nucleosome position and chromatin structure is independent of Foxa1 and Foxa2 in the adult liver.

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References

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

    Article  CAS  PubMed  Google Scholar 

  2. Shivaswamy, S. et al. Dynamic remodeling of individual nucleosomes across a eukaryotic genome in response to transcriptional perturbation. PLoS Biol. 6, e65 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  3. 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 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. McPherson, C.E., Shim, E.Y., Friedman, D.S. & Zaret, K.S. An active tissue-specific enhancer and bound transcription factors existing in a precisely positioned nucleosomal array. Cell 75, 387–398 (1993).

    Article  CAS  PubMed  Google Scholar 

  6. Chen, H., Li, B. & Workman, J.L. A histone-binding protein, nucleoplasmin, stimulates transcription factor binding to nucleosomes and factor-induced nucleosome disassembly. EMBO J. 13, 380–390 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Li, B., Adams, C.C. & Workman, J.L. Nucleosome binding by the constitutive transcription factor Sp1. J. Biol. Chem. 269, 7756–7763 (1994).

    CAS  PubMed  Google Scholar 

  8. Kaestner, K.H., Hiemisch, H. & Schutz, G. Targeted disruption of the gene encoding hepatocyte nuclear factor 3γ results in reduced transcription of hepatocyte-specific genes. Mol. Cell. Biol. 18, 4245–4251 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Shen, W., Scearce, L.M., Brestelli, J.E., Sund, N.J. & Kaestner, K.H. Foxa3 (hepatocyte nuclear factor 3γ) is required for the regulation of hepatic GLUT2 expression and the maintenance of glucose homeostasis during a prolonged fast. J. Biol. Chem. 276, 42812–42817 (2001).

    Article  CAS  PubMed  Google Scholar 

  10. Lee, C.S., Friedman, J.R., Fulmer, J.T. & Kaestner, K.H. The initiation of liver development is dependent on Foxa transcription factors. Nature 435, 944–947 (2005).

    Article  CAS  PubMed  Google Scholar 

  11. Li, Z. et al. Foxa1 and Foxa2 regulate bile duct development in mice. J. Clin. Invest. 119, 1537–1545 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Zaret, K. Developmental competence of the gut endoderm: genetic potentiation by GATA and HNF3/fork head proteins. Dev. Biol. 209, 1–10 (1999).

    Article  CAS  PubMed  Google Scholar 

  13. Hoffman, B.G. et al. Locus co-occupancy, nucleosome positioning, and H3K4me1 regulate the functionality of FOXA2-, HNF4A-, and PDX1-bound loci in islets and liver. Genome Res. 20, 1037–1051 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Gardiner-Garden, M. & Frommer, M. CpG islands in vertebrate genomes. J. Mol. Biol. 196, 261–282 (1987).

    Article  CAS  PubMed  Google Scholar 

  15. Kundu, T.K. & Rao, M.R. CpG islands in chromatin organization and gene expression. J. Biochem. 125, 217–222 (1999).

    Article  CAS  PubMed  Google Scholar 

  16. Yaragatti, M., Basilico, C. & Dailey, L. Identification of active transcriptional regulatory modules by the functional assay of DNA from nucleosome-free regions. Genome Res. 18, 930–938 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Lai, E., Prezioso, V.R., Tao, W.F., Chen, W.S. & Darnell, J.E. Jr. Hepatocyte nuclear factor 3 α belongs to a gene family in mammals that is homologous to the Drosophila homeotic gene fork head. Genes Dev. 5, 416–427 (1991).

    Article  CAS  PubMed  Google Scholar 

  18. Tuteja, G., Jensen, S.T., White, P. & Kaestner, K.H. Cis-regulatory modules in the mammalian liver: composition depends on strength of Foxa2 consensus site. Nucleic Acids Res. 36, 4149–4157 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. 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 

  20. Xu, J. et al. Transcriptional competence and the active marking of tissue-specific enhancers by defined transcription factors in embryonic and induced pluripotent stem cells. Genes Dev. 23, 2824–2838 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Chodavarapu, R.K. et al. Relationship between nucleosome positioning and DNA methylation. Nature 466, 388–392 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Sutton, J. et al. Genesis, a winged helix transcriptional repressor with expression restricted to embryonic stem cells. J. Biol. Chem. 271, 23126–23133 (1996).

    Article  CAS  PubMed  Google Scholar 

  23. Fleischmann, G., Filipski, R. & Elgin, S.C. Isolation and distribution of a Drosophila protein preferentially associated with inactive regions of the genome. Chromosoma 96, 83–90 (1987).

    Article  CAS  PubMed  Google Scholar 

  24. Lachner, M., O'Carroll, D., Rea, S., Mechtler, K. & Jenuwein, T. Methylation of histone H3 lysine 9 creates a binding site for HP1 proteins. Nature 410, 116–120 (2001).

    Article  CAS  PubMed  Google Scholar 

  25. Visel, A. et al. ChIP-seq accurately predicts tissue-specific activity of enhancers. Nature 457, 854–858 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. 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 

  27. Greenbaum, L.E. et al. CCAAT enhancer–binding protein β is required for normal hepatocyte proliferation in mice after partial hepatectomy. J. Clin. Invest. 102, 996–1007 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Morrison, A.J., Sardet, C. & Herrera, R.E. Retinoblastoma protein transcriptional repression through histone deacetylation of a single nucleosome. Mol. Cell. Biol. 22, 856–865 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Rubins, N.E. et al. Transcriptional networks in the liver: hepatocyte nuclear factor 6 function is largely independent of Foxa2. Mol. Cell. Biol. 25, 7069–7077 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Tuteja, G., White, P., Schug, J. & Kaestner, K.H. Extracting transcription factor targets from ChIP-Seq data. Nucleic Acids Res. 37, e113 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  31. Crooks, G.E., Hon, G., Chandonia, J.M. & Brenner, S.E. WebLogo: a sequence logo generator. Genome Res. 14, 1188–1190 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Gao, N. et al. Dynamic regulation of Pdx1 enhancers by Foxa1 and Foxa2 is essential for pancreas development. Genes Dev. 22, 3435–3448 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. 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

We thank A. Fox, O. Smirnova, K. Brondell, A. Chen, A. Riblett and J. LaRossa (University of Pennsylvania) for excellent technical support. This study was supported by the US National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (P01-DK049210 to K.H.K.). Z.L. was supported by National Sciences and Engineering Research Council of Canada and Juvenile Diabetes Research Foundation postdoctoral fellowship awards. We would like to acknowledge support of the Institute for Diabetes, Obesity, and Metabolism Functional Genomics Core by an NIDDK Research Center grant (P30DK19525).

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Authors and Affiliations

  1. Department of Genetics, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA

    Zhaoyu Li, Jonathan Schug, Geetu Tuteja, Peter White & Klaus H Kaestner

  2. Institute of Diabetes, Obesity and Metabolism, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA

    Zhaoyu Li, Jonathan Schug, Geetu Tuteja, Peter White & Klaus H Kaestner

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  1. Zhaoyu Li
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Contributions

Z.L. did the majority of experiments and computational analyses. J.S., P.W. and G.T. did a part of the experiments and computational analyses. K.H.K. directed the whole study. Z.L. and K.H.K. designed the experiments and wrote the manuscript.

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Correspondence to Klaus H Kaestner.

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Li, Z., Schug, J., Tuteja, G. et al. The nucleosome map of the mammalian liver. Nat Struct Mol Biol 18, 742–746 (2011). https://doi.org/10.1038/nsmb.2060

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