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