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.

Broad H3K4me3 is associated with increased transcription elongation and enhancer activity at tumor-suppressor genes

Abstract

Tumor suppressors are mostly defined by inactivating mutations in tumors, yet little is known about their epigenetic features in normal cells. Through integrative analysis of 1,134 genome-wide epigenetic profiles, mutations from >8,200 tumor-normal pairs and our experimental data from clinical samples, we discovered broad peaks for trimethylation of histone H3 at lysine 4 (H3K4me3; wider than 4 kb) as the first epigenetic signature for tumor suppressors in normal cells. Broad H3K4me3 is associated with increased transcription elongation and enhancer activity, which together lead to exceptionally high gene expression, and is distinct from other broad epigenetic features, such as super-enhancers. Genes with broad H3K4me3 peaks conserved across normal cells may represent pan-cancer tumor suppressors, such as TP53 and PTEN, whereas genes with cell type–specific broad H3K4me3 peaks may represent cell identity genes and cell type–specific tumor suppressors. Furthermore, widespread shortening of broad H3K4me3 peaks in cancers is associated with repression of tumor suppressors. Thus, the broad H3K4me3 epigenetic signature provides mutation-independent information for the discovery and characterization of new tumor suppressors.

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

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Broad H3K4me3 peaks in human CD4+ T cells mark tumor-suppressor and cell identity genes.
Figure 2: Most promoter-associated epigenetic marks coincide with broad H3K4me3 peaks in human CD4+ T cells.
Figure 3: Broad H3K4me3 peaks are associated with increased transcription elongation.
Figure 4: Broad H3K4me3 peaks have strong enhancer activity in human CD4+ T cells.
Figure 5: Broad H3K4me3 peaks at tumor suppressors is conserved across ENCODE normal cell types.
Figure 6: Widespread shortening of broad H3K4me3 peaks at tumor suppressors.
Figure 7: Shortening of broad H3K4me3 peaks in lung tumors.
Figure 8: Functional characterization of putative new tumor suppressors defined by conserved broad H3K4me3 peaks.

Accession codes

Primary accessions

Gene Expression Omnibus

References

  1. Weinstein, J.N. et al. The Cancer Genome Atlas Pan-Cancer analysis project. Nat. Genet. 45, 1113–1120 (2013).

    Article  Google Scholar 

  2. Davoli, T. et al. Cumulative haploinsufficiency and triplosensitivity drive aneuploidy patterns and shape the cancer genome. Cell 155, 948–962 (2013).

    Article  CAS  Google Scholar 

  3. Vogelstein, B. et al. Cancer genome landscapes. Science 339, 1546–1558 (2013).

    Article  CAS  Google Scholar 

  4. De, S. & Michor, F. DNA replication timing and long-range DNA interactions predict mutational landscapes of cancer genomes. Nat. Biotechnol. 29, 1103–1108 (2011).

    Article  CAS  Google Scholar 

  5. Schuster-Böckler, B. & Lehner, B. Chromatin organization is a major influence on regional mutation rates in human cancer cells. Nature 488, 504–507 (2012).

    Article  Google Scholar 

  6. Lawrence, M.S. et al. Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature 499, 214–218 (2013).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  8. Lauberth, S.M. et al. H3K4me3 interactions with TAF3 regulate preinitiation complex assembly and selective gene activation. Cell 152, 1021–1036 (2013).

    Article  CAS  Google Scholar 

  9. Zhao, X.D. et al. Whole-genome mapping of histone H3 Lys4 and 27 trimethylations reveals distinct genomic compartments in human embryonic stem cells. Cell Stem Cell 1, 286–298 (2007).

    Article  CAS  Google Scholar 

  10. Sims, R.J. et al. Recognition of trimethylated histone H3 lysine 4 facilitates the recruitment of transcription postinitiation factors and pre-mRNA splicing. Mol. Cell 28, 665–676 (2007).

    Article  CAS  Google Scholar 

  11. Borde, V. et al. Histone H3 lysine 4 trimethylation marks meiotic recombination initiation sites. EMBO J. 28, 99–111 (2009).

    Article  CAS  Google Scholar 

  12. Pena, P.V., Hom, R.A., Hung, T., Lin, H. & Kuo, A.J. Histone H3K4me3 binding is required for the DNA repair and apoptotic activities of ING1 tumor suppressor. J. Mol. Biol. 380, 303–312 (2008).

    Article  CAS  Google Scholar 

  13. Calo, E. & Wysocka, J. Modification of enhancer chromatin: what, how, and why? Mol. Cell 49, 825–837 (2013).

    Article  CAS  Google Scholar 

  14. Whyte, W.A. et al. Master transcription factors and Mediator establish super-enhancers at key cell identity genes. Cell 153, 307–319 (2013).

    Article  CAS  Google Scholar 

  15. Hnisz, D. et al. Super-enhancers in the control of cell identity and disease. Cell 155, 934–947 (2013).

    Article  CAS  Google Scholar 

  16. Lovén, J. et al. Selective inhibition of tumor oncogenes by disruption of super-enhancers. Cell 153, 320–334 (2013).

    Article  Google Scholar 

  17. Virely, C. et al. Haploinsufficiency of the IKZF1 (IKAROS) tumor suppressor gene cooperates with BCR-ABL in a transgenic model of acute lymphoblastic leukemia. Leukemia 24, 1200–1204 (2010).

    Article  CAS  Google Scholar 

  18. Georgopoulos, K., Winandy, S. & Avitahl, N. The role of the Ikaros gene in lymphocyte development and homeostasis. Annu. Rev. Immunol. 15, 155–176 (1997).

    Article  CAS  Google Scholar 

  19. Dail, M. et al. Mutant Ikzf1, KrasG12D, and Notch1 cooperate in T lineage leukemogenesis and modulate responses to targeted agents. Proc. Natl. Acad. Sci. USA 107, 5106–5111 (2010).

    Article  CAS  Google Scholar 

  20. Gutierrez, A. et al. High frequency of PTEN, PI3K, and AKT abnormalities in T-cell acute lymphoblastic leukemia. Blood 114, 647–650 (2009).

    Article  CAS  Google Scholar 

  21. Mendes, R.D. et al. PTEN microdeletions in T-cell acute lymphoblastic leukemia are caused by illegitimate RAG-mediated recombination events. Blood 124, 567–578 (2014).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  23. Eisenberg, E. & Levanon, E.Y. Human housekeeping genes, revisited. Trends Genet. 29, 569–574 (2013).

    Article  CAS  Google Scholar 

  24. Yasuo, K. & Shigeo, O. Regulation of mitochondrial ATP synthesis in mammalian cells by transcriptional control. Int. J. Biochem. 22, 219–229 (1990).

    Article  Google Scholar 

  25. Smolle, M. & Workman, J.L. Transcription-associated histone modifications and cryptic transcription. Biochim. Biophys. Acta 1829, 84–97 (2013).

    Article  CAS  Google Scholar 

  26. Rahl, P.B. et al. c-Myc regulates transcriptional pause release. Cell 141, 432–445 (2010).

    Article  CAS  Google Scholar 

  27. Glover-Cutter, K., Kim, S., Espinosa, J. & Bentley, D.L. RNA polymerase II pauses and associates with pre-mRNA processing factors at both ends of genes. Nat. Struct. Mol. Biol. 15, 71–78 (2008).

    Article  CAS  Google Scholar 

  28. Jonkers, I., Kwak, H. & Lis, J.T. Genome-wide dynamics of Pol II elongation and its interplay with promoter proximal pausing, chromatin, and exons. eLife 3, e02407 (2014).

    Article  Google Scholar 

  29. Veloso, A. et al. Rate of elongation by RNA polymerase II is associated with specific gene features and epigenetic modifications. Genome Res. 24, 896–905 (2014).

    Article  CAS  Google Scholar 

  30. Nie, Z. et al. c-Myc is a universal amplifier of expressed genes in lymphocytes and embryonic stem cells. Cell 151, 68–79 (2012).

    Article  CAS  Google Scholar 

  31. Lin, C.Y. et al. Transcriptional amplification in tumor cells with elevated c-Myc. Cell 151, 56–67 (2012).

    Article  CAS  Google Scholar 

  32. Chao, S.H. & Price, D.H. Flavopiridol inactivates P-TEFb and blocks most RNA polymerase II transcription in vivo. J. Biol. Chem. 276, 31793–31799 (2001).

    Article  CAS  Google Scholar 

  33. Kheradpour, P. & Kellis, M. Systematic discovery and characterization of regulatory motifs in ENCODE TF binding experiments. Nucleic Acids Res. 42, 2976–2987 (2014).

    Article  CAS  Google Scholar 

  34. Wang, J. et al. Sequence features and chromatin structure around the genomic regions bound by 119 human transcription factors. Genome Res. 22, 1798–1812 (2012).

    Article  CAS  Google Scholar 

  35. Barrett, C.W. et al. Tumor suppressor function of the plasma glutathione peroxidase Gpx3 in colitis-associated carcinoma. Cancer Res. 73, 1245–1255 (2013).

    Article  CAS  Google Scholar 

  36. Matthew, E.M. et al. The p53 target Plk2 interacts with TSC proteins impacting mTOR signaling, tumor growth and chemosensitivity under hypoxic conditions. Cell Cycle 8, 4168–4175 (2009).

    Article  CAS  Google Scholar 

  37. Coley, H.M. et al. Polo like kinase 2 tumour suppressor and cancer biomarker: new perspectives on drug sensitivity/resistance in ovarian cancer. Oncotarget 3, 78–83 (2012).

    Article  Google Scholar 

  38. Smith, P., Syed, N. & Crook, T. Epigenetic inactivation implies a tumor suppressor function in hematologic malignancies for Polo-like kinase 2 but not Polo-like kinase 3. Cell Cycle 5, 1262–1264 (2006).

    Article  CAS  Google Scholar 

  39. Rincon-Arano, H., Halow, J., Delrow, J.J., Parkhurst, S.M. & Groudine, M. UpSET recruits HDAC complexes and restricts chromatin accessibility and acetylation at promoter regions. Cell 151, 1214–1228 (2012).

    Article  CAS  Google Scholar 

  40. Ali, M. et al. Molecular basis for chromatin binding and regulation of MLL5. Proc. Natl. Acad. Sci. USA 110, 11296–11301 (2013).

    Article  CAS  Google Scholar 

  41. Xie, W. et al. Epigenomic analysis of multilineage differentiation of human embryonic stem cells. Cell 153, 1134–1148 (2013).

    Article  CAS  Google Scholar 

  42. Jeong, M. et al. Large conserved domains of low DNA methylation maintained by Dnmt3a. Nat. Genet. 46, 17–23 (2014).

    Article  CAS  Google Scholar 

  43. Pekowska, A., Benoukraf, T., Ferrier, P. & Spicuglia, S. A unique H3K4me2 profile marks tissue-specific gene regulation. Genome Res. 20, 1493–1502 (2010).

    Article  CAS  Google Scholar 

  44. Shulha, H.P. et al. Epigenetic signatures of autism: trimethylated H3K4 landscapes in prefrontal neurons. Arch. Gen. Psychiatry 69, 314–324 (2012).

    Article  CAS  Google Scholar 

  45. Benayoun, B.A. et al. H3K4me3 breadth is linked to cell identity and transcriptional consistency. Cell 158, 673–688 (2014).

    Article  CAS  Google Scholar 

  46. Chen, Z. et al. Agonist and antagonist switch DNA motifs recognized by human androgen receptor in prostate cancer. EMBO J. 34, 502–516 (2015).

    Article  CAS  Google Scholar 

  47. Wang, Q. et al. Androgen receptor regulates a distinct transcription program in androgen-independent prostate cancer. Cell 138, 245–256 (2009).

    Article  CAS  Google Scholar 

  48. Chen, K. et al. DANPOS: Dynamic Analysis of Nucleosome Position and Occupancy by Sequencing. Genome Res. 23, 341–351 (2013).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We are grateful to M. Luo, M. Goodell, L. Donehower, T. Westbrook and A. Brunet for helpful discussions. This work was supported by the US National Institutes of Health (NIH) grants R01HG007538 and R01CA193466, Cancer Prevention Research Institute of Texas (CPRIT) grants RP110471 and RP150292 (W.L.), and US NIH grant R01CA151979, US Department of Defense grant W81XWH-12-1-0615 and US NIH grant U54CA113001 (Q.W.). X.S. is an inaugural MD Anderson Cancer Center R. Lee Clark Fellow.

Author information

Authors and Affiliations

Authors

Contributions

K.C. and W.L. conceived the project, designed the experiments and performed the data analysis. Z.C., D.W. and Q.W. designed and performed the experiments. L.Z. designed the experiments and performed the data analysis. X.L., J.S., Y.X. and Z.X. analyzed the data. K.C., Q.W. and W.L. interpreted the data and wrote the manuscript with comments from B.R., X.C. and X.S.

Corresponding authors

Correspondence to Qianben Wang or Wei Li.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–24. (PDF 2813 kb)

Supplementary Table 1

A list of public data sets used in this study. (XLS 530 kb)

Supplementary Table 2

Number of genes assigned with broad H3K4me3 peaks in each sample. (XLS 67 kb)

Supplementary Table 3

H3K4me3 peak width at each gene in each sample from ENCODE and Roadmap Epigenomics. (XLS 28472 kb)

Supplementary Table 4

Broad H3K4me3 peaks at tumor suppressors that are shortened, lengthened or stable between 105 normal and 63 cancer samples. (XLS 29 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Chen, K., Chen, Z., Wu, D. et al. Broad H3K4me3 is associated with increased transcription elongation and enhancer activity at tumor-suppressor genes. Nat Genet 47, 1149–1157 (2015). https://doi.org/10.1038/ng.3385

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng.3385

This article is cited by

Search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer