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.

  • Analysis
  • Published:

Reciprocal intronic and exonic histone modification regions in humans

Nature Structural & Molecular Biology volume 17, pages 1495–1499 (2010)Cite this article

Subjects

Abstract

While much attention has been focused on chromatin at promoters and exons, human genes are mostly composed of intronic sequences. Analyzing published surveys of nucleosomes and 41 chromatin marks in humans, we identified histone modifications specifically associated with 5′ intronic sequences, distinguishable from promoter marks and bulk nucleosomes. These intronic marks were spatially reciprocal to trimethylated histone H3 Lys36 (H3K36me3), typically transitioning near internal exons. Several marks transitioned near bona fide exons, but not near nucleosomes at exon-like sequences. Therefore, we examined whether splicing affects histone marking. Even with considerable changes in regulated alternative splicing, histone marks were stable. Notably, these findings are consistent with exon definition influencing histone marks. In summary, we show that the location of many intragenic marks in humans can be distilled into a simple organizing principle: association with 5′ intronic or 3′ exonic regions.

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

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

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

Figure 1: Groups of histone marks revealed by PCA.
Figure 2: Intragenic histone modification regions reflect gene architecture.
Figure 3: Histone modification profiles at the alternatively spliced exon of YPEL5 are similar between caffeine-treated SW620 cells expressing different YPEL5 mRNA isoforms.
Figure 4: Histone modification profiles at the alternatively spliced exons of CD45 are similar between B-cell lines stably expressing different CD45 mRNA isoforms.

Similar content being viewed by others

References

  1. Berger, S.L. The complex language of chromatin regulation during transcription. Nature 447, 407–412 (2007).

    Article  CAS  Google Scholar 

  2. Kouzarides, T. Chromatin modifications and their function. Cell 128, 693–705 (2007).

    Article  CAS  Google Scholar 

  3. Loyola, A. & Almouzni, G. Marking histone H3 variants: how, when and why? Trends Biochem. Sci. 32, 425–433 (2007).

    Article  CAS  Google Scholar 

  4. Lee, B.M. & Mahadevan, L.C. Stability of histone modifications across mammalian genomes: implications for 'epigenetic' marking. J. Cell. Biochem. 108, 22–34 (2009).

    Article  CAS  Google Scholar 

  5. Talbert, P.B. & Henikoff, S. Histone variants–ancient wrap artists of the epigenome. Nat. Rev. Mol. Cell Biol. 11, 264–275 (2010).

    Article  CAS  Google Scholar 

  6. Vermeulen, M. et al. Selective anchoring of TFIID to nucleosomes by trimethylation of histone H3 lysine 4. Cell 131, 58–69 (2007).

    Article  CAS  Google Scholar 

  7. Perales, R. & Bentley, D. “Cotranscriptionality”: the transcription elongation complex as a nexus for nuclear transactions. Mol. Cell 36, 178–191 (2009).

    Article  CAS  Google Scholar 

  8. Zhong, X.Y., Wang, P., Han, J., Rosenfeld, M.G. & Fu, X. SR proteins in vertical integration of gene expression from transcription to RNA processing to translation. Mol. Cell 35, 1–10 (2009).

    Article  CAS  Google Scholar 

  9. Brès, V., Yoshida, T., Pickle, L. & Jones, K.A. SKIP interacts with c-Myc and Menin to promote HIV-1 Tat transactivation. Mol. Cell 36, 75–87 (2009).

    Article  Google Scholar 

  10. Li, B., Carey, M. & Workman, J.L. The role of chromatin during transcription. Cell 128, 707–719 (2007).

    Article  CAS  Google Scholar 

  11. Yoh, S.M., Lucas, J.S. & Jones, K.A. The Iws1:Spt6:CTD complex controls cotranscriptional mRNA biosynthesis and HYPB/Setd2-mediated histone H3K36 methylation. Genes Dev. 22, 3422–3434 (2008).

    Article  CAS  Google Scholar 

  12. Luco, R.F. et al. Regulation of alternative splicing by histone modifications. Science 327, 996–1000 (2010).

    Article  CAS  Google Scholar 

  13. Andersson, R., Enroth, S., Rada-Iglesias, A., Wadelius, C. & Komorowski, J. Nucleosomes are well positioned in exons and carry characteristic histone modifications. Genome Res. 19, 1732–1741 (2009).

    Article  CAS  Google Scholar 

  14. Hon, G., Wang, W. & Ren, B. Discovery and annotation of functional chromatin signatures in the human genome. PLOS Comput. Biol. 5, e1000566 (2009).

    Article  Google Scholar 

  15. Kolasinska-Zwierz, P. et al. Differential chromatin marking of introns and expressed exons by H3K36me3. Nat. Genet. 41, 376–381 (2009).

    Article  CAS  Google Scholar 

  16. Nahkuri, S., Taft, R.J. & Mattick, J.S. Nucleosomes are preferentially positioned at exons in somatic and sperm cells. Cell Cycle 8, 3420–3424 (2009).

    Article  CAS  Google Scholar 

  17. Schwartz, S., Meshorer, E. & Ast, G. Chromatin organization marks exon-intron structure. Nat. Struct. Mol. Biol. 16, 990–995 (2009).

    Article  CAS  Google Scholar 

  18. Spies, N., Nielsen, C.B., Padgett, R.A. & Burge, C.B. Biased chromatin signatures around polyadenylation sites and exons. Mol. Cell 36, 245–254 (2009).

    Article  CAS  Google Scholar 

  19. Tilgner, H. et al. Nucleosome positioning as a determinant of exon recognition. Nat. Struct. Mol. Biol. 16, 996–1001 (2009).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  22. Shema, E. et al. The histone H2B-specific ubiquitin ligase RNF20/hBRE1 acts as a putative tumor suppressor through selective regulation of gene expression. Genes Dev. 22, 2664–2676 (2008).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  24. 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  Google Scholar 

  25. McGhee, J.D. & Felsenfeld, G. Another potential artifact in the study of nucleosome phasing by chromatin digestion with micrococcal nuclease. Cell 32, 1205–1215 (1983).

    Article  CAS  Google Scholar 

  26. Dohm, J.C., Lottaz, C., Borodina, T. & Himmelbauer, H. Substantial biases in ultra-short read data sets from high-throughput DNA sequencing. Nucleic Acids Res. 36, e105 (2008).

    Article  Google Scholar 

  27. Jin, C. & Felsenfeld, G. Nucleosome stability mediated by histone variants H3.3 and H2A.Z. Genes Dev. 21, 1519–1529 (2007).

    Article  CAS  Google Scholar 

  28. Wahl, M.C., Will, C.L. & Lührmann, R. The spliceosome: design principles of a dynamic RNP machine. Cell 136, 701–718 (2009).

    Article  CAS  Google Scholar 

  29. Chen, M. & Manley, J.L. Mechanisms of alternative splicing regulation: insights from molecular and genomics approaches. Nat. Rev. Mol. Cell Biol. 10, 741–754 (2009).

    Article  CAS  Google Scholar 

  30. Shi, J., Hu, Z., Pabon, K. & Scotto, K.W. Caffeine regulates alternative splicing in a subset of cancer-associated genes: a role for SC35. Mol. Cell. Biol. 28, 883–895 (2008).

    Article  CAS  Google Scholar 

  31. Oberdoerffer, S. et al. Regulation of CD45 alternative splicing by heterogeneous ribonucleoprotein, hnRNPLL. Science 321, 686–691 (2008).

    Article  CAS  Google Scholar 

  32. Topp, J.D., Jackson, J., Melton, A.A. & Lynch, K.W. A cell-based screen for splicing regulators identifies hnRNP LL as a distinct signal-induced repressor of CD45 variable exon 4. RNA 14, 2038–2049 (2008).

    Article  CAS  Google Scholar 

  33. Wu, Z. et al. Memory T cell RNA rearrangement programmed by heterogeneous nuclear ribonucleoprotein hnRNPLL. Immunity 29, 863–875 (2008).

    Article  CAS  Google Scholar 

  34. Edmunds, J.W., Mahadevan, L.C. & Clayton, A.L. Dynamic histone H3 methylation during gene induction: HYPB/Setd2 mediates all H3K36 trimethylation. EMBO J. 27, 406–420 (2008).

    Article  CAS  Google Scholar 

  35. House, A.E. & Lynch, K.W. An exonic splicing silencer represses spliceosome assembly after ATP-dependent exon recognition. Nat. Struct. Mol. Biol. 13, 937–944 (2006).

    Article  CAS  Google Scholar 

  36. Raisner, R.M. et al. Histone variant H2A.Z marks the 5′ ends of both active and inactive genes in euchromatin. Cell 123, 233–248 (2005).

    Article  CAS  Google Scholar 

  37. Kouskouti, A. & Talianidis, I. Histone modifications defining active genes persist after transcriptional and mitotic inactivation. EMBO J. 24, 347–357 (2005).

    Article  CAS  Google Scholar 

  38. Guenther, M.G., Levine, S.S., Boyer, L.A., Jaenisch, R. & Young, R.A. A chromatin landmark and transcription initiation at most promoters in human cells. Cell 130, 77–88 (2007).

    Article  CAS  Google Scholar 

  39. Latham, J.A. & Dent, S.Y.R. Cross-regulation of histone modifications. Nat. Struct. Mol. Biol. 14, 1017–1024 (2007).

    Article  CAS  Google Scholar 

  40. McGinty, R.K., Kim, J., Chatterjee, C., Roeder, R.G. & Muir, T.W. Chemically ubiquitylated histone H2B stimulates hDot1L-mediated intranucleosomal methylation. Nature 453, 812–816 (2008).

    Article  CAS  Google Scholar 

  41. Mohan, M. et al. Linking H3K79 trimethylation to Wnt signaling through a novel Dot1-containing complex (DotCom). Genes Dev. 24, 574–589 (2010).

    Article  CAS  Google Scholar 

  42. Kim, J., Hake, S.B. & Roeder, R.G. The human homolog of yeast BRE1 functions as a transcriptional coactivator through direct activator interactions. Mol. Cell 20, 759–770 (2005).

    Article  CAS  Google Scholar 

  43. Kim, J. et al. RAD6-Mediated transcription-coupled H2B ubiquitylation directly stimulates H3K4 methylation in human cells. Cell 137, 459–471 (2009).

    Article  CAS  Google Scholar 

  44. Kim, T. & Buratowski, S. Dimethylation of H3K4 by Set1 recruits the Set3 histone deacetylase complex to 5′ transcribed regions. Cell 137, 259–272 (2009).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank the following for kindly providing reagents and data: S. Oberdoerffer and A. Rao (Harvard Medical School) for B-cell lines, N. Spies and C. Burge (MIT) for ECR locations, and E. Shema and M. Oren (Weizmann Institute of Science) for H2Bub ChIP-seq data. We also thank H. Madhani and J. Steitz for critical reading of the manuscript and the Guthrie, Yamamoto and Panning groups for helpful discussions. J.T.H. and A.M.P. were supported by individual ARCS Foundation Scholarships. Research support was provided by US National Institutes of Health grants GM21119 to C.G. and CA020535 to K.R.Y. C.G. is an American Cancer Society Research Professor of Molecular Genetics, and K.R.Y. is a consultant with Merck & Co.

Author information

Author notes

  1. Jason T Huff and Alex M Plocik: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Cellular and Molecular Pharmacology, University of California, San Francisco, California, USA

    Jason T Huff & Keith R Yamamoto

  2. Department of Biochemistry and Biophysics, University of California, San Francisco, California, USA

    Alex M Plocik & Christine Guthrie

Authors
  1. Jason T Huff
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Alex M Plocik
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Christine Guthrie
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Keith R Yamamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

J.T.H. and A.M.P. designed and performed the analyses and experiments. J.T.H., A.M.P., C.G. and K.R.Y. wrote the manuscript.

Corresponding authors

Correspondence to Christine Guthrie or Keith R Yamamoto.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figs. 1-7 and Supplementary Table 1 (PDF 5571 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Huff, J., Plocik, A., Guthrie, C. et al. Reciprocal intronic and exonic histone modification regions in humans. Nat Struct Mol Biol 17, 1495–1499 (2010). https://doi.org/10.1038/nsmb.1924

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nsmb.1924

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