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Nat Genet. 2015 Oct;47(10):1149-57. doi: 10.1038/ng.3385. Epub 2015 Aug 24.

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

Chen K1,2,3,4,5, Chen Z6,7, Wu D6,7, Zhang L8, Lin X1,2,9, Su J1,2, Rodriguez B1,2, Xi Y1,2, Xia Z1,2, Chen X2, Shi X10,11, Wang Q6,7, Li W1,2.

Author information

1
Division of Biostatistics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas, USA.
2
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA.
3
Institute for Academic Medicine, Methodist Hospital Research Institute, Houston, Texas, USA.
4
Center for Cardiovascular Regeneration, Department of Cardiovascular Sciences, Methodist Hospital Research Institute, Houston, Texas, USA.
5
Weill Cornell Medical College, Cornell University, New York, New York, USA.
6
Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University College of Medicine, Columbus, Ohio, USA.
7
Comprehensive Cancer Center, The Ohio State University College of Medicine, Columbus, Ohio, USA.
8
Ocular Surface Center, Cullen Eye Institute, Department of Ophthalmology, Baylor College of Medicine, Houston, Texas, USA.
9
Department of Bioinformatics, School of Life Sciences and Technology, Tongji University, Shanghai, China.
10
Department of Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
11
Center for Cancer Epigenetics, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

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.

PMID:
26301496
PMCID:
PMC4780747
DOI:
10.1038/ng.3385
[Indexed for MEDLINE]
Free PMC Article

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