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Determinants of nucleosome organization in primary human cells

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Abstract

Nucleosomes are the basic packaging units of chromatin, modulating accessibility of regulatory proteins to DNA and thus influencing eukaryotic gene regulation. Elaborate chromatin remodelling mechanisms have evolved that govern nucleosome organization at promoters, regulatory elements, and other functional regions in the genome1. Analyses of chromatin landscape have uncovered a variety of mechanisms, including DNA sequence preferences, that can influence nucleosome positions2,3,4. To identify major determinants of nucleosome organization in the human genome, we used deep sequencing to map nucleosome positions in three primary human cell types and in vitro. A majority of the genome showed substantial flexibility of nucleosome positions, whereas a small fraction showed reproducibly positioned nucleosomes. Certain sites that position in vitro can anchor the formation of nucleosomal arrays that have cell type-specific spacing in vivo. Our results unveil an interplay of sequence-based nucleosome preferences and non-nucleosomal factors in determining nucleosome organization within mammalian cells.

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Figure 1: Global parameters of cell-specific nucleosome phasing and positioning in human.
Figure 2: Transcription and chromatin modification-dependent nucleosome spacing.
Figure 3: Sequence signals that drive nucleosome positioning.
Figure 4: Influence of gene regulatory function on nucleosome positioning.

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Accession codes

Primary accessions

Sequence Read Archive

Data deposits

All sequence data were submitted to Sequence Read Archive (accession number GSE25133). Sites containing strongly positioned in vitro nucleosomes are available as a supplementary data file.

Change history

  • 23 June 2011

    A figure citation was corrected in the paragraph beginning, 'To explore how regulatory factors interact...".

References

  1. Mellor, J. The dynamics of chromatin remodeling at promoters. Mol. Cell 19, 147–157 (2005)

    Article  CAS  Google Scholar 

  2. Radman-Livaja, M. & Rando, O. J. Nucleosome positioning: how is it established, and why does it matter? Dev. Biol. 339, 258–266 (2010)

    Article  CAS  Google Scholar 

  3. Kaplan, N. et al. The DNA-encoded nucleosome organization of a eukaryotic genome. Nature 458, 362–366 (2009)

    Article  ADS  CAS  Google Scholar 

  4. Berstein, B. E., Liu, C. L., Humphrey, E. L., Perlstein, E. O. & Schreiber, S. L. Global nucleosome occupancy in yeast. Genome Biol. 5, R62 (2004)

    Article  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

  6. Johnson, S. M., Tan, F. J., McCullough, H. L., Riordan, D. P. & Fire, A. Z. Flexibility and constraint in the nucleosome core landscape of Caenorhabditis elegans chromatin. Genome Res. 16, 1505–1516 (2006)

    Article  CAS  Google Scholar 

  7. 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  Google Scholar 

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

    Article  CAS  Google Scholar 

  9. Trifonov, E. N. & Sussman, J. L. The pitch of chromatin DNA is reflected in it its nucleotide sequence. Proc. Natl Acad. Sci. USA 77, 3816–3820 (1980)

    Article  ADS  CAS  Google Scholar 

  10. Kornberg, R. D. Structure of chromatin. Ann. Rev. Biochem. 46, 931–954 (1977)

    Article  CAS  Google Scholar 

  11. Widom, J. A relationship between the helical twist of DNA and the ordered positioning of nucleosomes in all eukaryotic cells. Proc. Natl Acad. Sci. USA 89, 1095–1099 (1992)

    Article  ADS  CAS  Google Scholar 

  12. Schlegel, R. A., Haye, K. R., Litwack, A. H. & Phelps, B. M. Nucleosome repeat lengths in the definitive erythroid series of the adult chicken. Biochim. Biophys. Acta 606, 316–330 (1980)

    Article  CAS  Google Scholar 

  13. Fan, Y. et al. Histone H1 depletion in mammals alters global chromatin structure but causes specific changes in gene regulation. Cell 29, 1199–1212 (2005)

    Article  Google Scholar 

  14. Mortazavi, A., Williams, B. A., McCue, K., Schaeffer, L. & Wold, B. Mapping and quantifying mammalian transcriptomes by RNA-Seq. Nature Methods 5, 621–628 (2008)

    Article  CAS  Google Scholar 

  15. Valouev, A. et al. Genome-wide analysis of transcription factor binding sites based on ChIP-Seq data. Nature Methods 5, 829–834 (2008)

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  17. Wang, Z. et al. Combinatorial patterns of histone acetylations and methylations in the human genome. Nature Genet. 40, 897–903 (2008)

    Article  CAS  Google Scholar 

  18. Satchwell, S. C., Drew, H. R. & Travers, A. A. Sequence periodicities in chicken nucleosome core DNA. J. Mol. Biol. 191, 659–675 (1986)

    Article  CAS  Google Scholar 

  19. Segal, E. et al. A genomic code for nucleosome positioning. Nature 442, 772–778 (2006)

    Article  ADS  CAS  Google Scholar 

  20. Hughes, A. & Rando, O. J. Chromatin ‘programming’ by sequence - is there more to the nucleosome code than %GC? J. Biol. 8, 96 (2009)

    Article  Google Scholar 

  21. Tillo, D. et al. High nucleosome occupancy is encoded at human regulatory sequences. PLoS ONE 5, e9129 (2010)

    Article  ADS  Google Scholar 

  22. 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  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  25. Gu, S. G. & Fire, A. Partitioning the C. elegans genome by nucleosome modification, occupancy, and positioning. Chromosoma 119, 73–87 (2010)

    Article  CAS  Google Scholar 

  26. Sasaki, S. et al. Chromatin-associated periodicity in genetic variation downstream of transcriptional start sites. Science 323, 401–404 (2009)

    Article  ADS  CAS  Google Scholar 

  27. Zhang, Y. et al. Intrinsic histone-DNA interactions are not the major determinant of nucleosome positions in vivo . Nature Struct. Mol. Biol. 16, 847–852 (2009)

    Article  CAS  Google Scholar 

  28. Field, Y. et al. Gene expression divergence in yeast is coupled to evolution of DNA-encoded nucleosome organization. Nature Genet. 41, 438–445 (2009)

    Article  CAS  Google Scholar 

  29. Chuddapah, S. et al. Global analysis of the insulator binding protein CTCF in chromatin barrier regions reveals demarcation of active and repressive domains. Genome Res. 19, 24–32 (2009)

    Article  Google Scholar 

  30. Fu, Y., Sinha, M., Peterson, C. L. & Weng, Z. The insulator binding protein CTCF positions 20 nucleosomes around its binding sites across the human genome. PLoS Genet. 4, e1000138 (2008)

    Article  Google Scholar 

  31. Albert, I. et al. Translational and rotational settings of H2A.Z nucleosomes across the Saccharomyces cerevisiae genome. Nature 446, 572–576 (2007)

    Article  ADS  CAS  Google Scholar 

  32. Wellinger, R. E. & Thoma, F. Nucleosome structure and positioning modulate nucleotide excision repair in the non-transcribed strand of an active gene. EMBO J. 16, 5046–5056 (1997)

    Article  CAS  Google Scholar 

  33. Sha, K. et al. Distributed probing of chromatin structure in vivo reveals pervasive chromatin accessibility for expressed and non-expressed genes during tissue differentiation in C. elegans . BMC Genomics 11, 465 (2010)

    Article  Google Scholar 

  34. Luger, K., Rechsteiner, T. J. & Richmond, T. J. Preparation of nucleosome core particle from recombinant histones. Methods Enzymol. 304, 3–19 (1999)

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported by the Stanford Genetics/Pathology Sequencing Initiative. We thank G. Narlikar for help with in vitro experiments, Life Technologies, especially J. Briggs, for help with generating sequencing data, P. Lacroute for help with sequence alignment, S. Galli for valuable discussions, L. Gracey for critical reading of the manuscript, and members of the Sidow and Fire labs for valuable feedback and discussions. Work in the Fire lab was partially supported by NIGMS (R01GM37706). A.V. was partially supported by an ENCODE subcontract to A.S. (NHGRI U01HG004695). S.M.J. was partially supported by the Stanford Genome Training program (NHGRI T32HG00044).

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Authors

Contributions

A.V., S.M.J., A.S. and A.Z.F. designed the experiments. S.M.J., A.V., C.L.S. and S.D.B. performed the experiments. A.V. designed and carried out analyses with input from A.S., A.Z.F. and S.M.J.; A.V., A.S. and A.Z.F. wrote the manuscript.

Corresponding authors

Correspondence to Andrew Z. Fire or Arend Sidow.

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The authors declare no competing financial interests.

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Valouev, A., Johnson, S., Boyd, S. et al. Determinants of nucleosome organization in primary human cells. Nature 474, 516–520 (2011). https://doi.org/10.1038/nature10002

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