title: 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.
authors: Division of Biostatistics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas, USA.|Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA.|Institute for Academic Medicine, Methodist Hospital Research Institute, Houston, Texas, USA.|Center for Cardiovascular Regeneration, Department of Cardiovascular Sciences, Methodist Hospital Research Institute, Houston, Texas, USA.|Weill Cornell Medical College, Cornell University, New York, New York, USA.
authors: Kaifu
authors: K
authors: Chen
authors: Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University College of Medicine, Columbus, Ohio, USA.|Comprehensive Cancer Center, The Ohio State University College of Medicine, Columbus, Ohio, USA.
authors: Zhong
authors: Z
authors: Chen
authors: Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University College of Medicine, Columbus, Ohio, USA.|Comprehensive Cancer Center, The Ohio State University College of Medicine, Columbus, Ohio, USA.
authors: Dayong
authors: D
authors: Wu
authors: Ocular Surface Center, Cullen Eye Institute, Department of Ophthalmology, Baylor College of Medicine, Houston, Texas, USA.
authors: Lili
authors: L
authors: Zhang
authors: Division of Biostatistics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas, USA.|Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA.|Department of Bioinformatics, School of Life Sciences and Technology, Tongji University, Shanghai, China.
authors: Xueqiu
authors: X
authors: Lin
authors: Division of Biostatistics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas, USA.|Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA.
authors: Jianzhong
authors: J
authors: Su
authors: Division of Biostatistics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas, USA.|Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA.
authors: Benjamin
authors: B
authors: Rodriguez
authors: Division of Biostatistics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas, USA.|Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA.
authors: Yuanxin
authors: Y
authors: Xi
authors: Division of Biostatistics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas, USA.|Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA.
authors: Zheng
authors: Z
authors: Xia
authors: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA.
authors: Xi
authors: X
authors: Chen
authors: Department of Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.|Center for Cancer Epigenetics, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors: Xiaobing
authors: X
authors: Shi
authors: Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University College of Medicine, Columbus, Ohio, USA.|Comprehensive Cancer Center, The Ohio State University College of Medicine, Columbus, Ohio, USA.
authors: Qianben
authors: Q
authors: Wang
authors: Division of Biostatistics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas, USA.|Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA.
authors: Wei
authors: http://orcid.org/0000-0001-9931-5990
authors: W
authors: Li
mesh_terms: D045744:Cell Line, Tumor; D004742:Enhancer Elements, Genetic; D044127:Epigenesis, Genetic; D016147:Genes, Tumor Suppressor; D006657:Histones / Q000378:metabolism*; D006801:Humans; D014158:Transcription, Genetic
chemical_list: D006657:Histones