Broad genic repression domains signify enhanced silencing of oncogenes

Dongyu Zhao, Lili Zhang (), Min Zhang, Bo Xia, Jie Lv, Xinlei Gao, Guangyu Wang, Qingshu Meng, Yang Yi, Sen Zhu, Alin S. Tomoiaga, Min Gyu Lee, John P. Cooke, Qi Cao () and Kaifu Chen ()
Additional contact information
Dongyu Zhao: Center for Bioinformatics and Computational Biology, Houston Methodist Research Institute
Lili Zhang: Houston Methodist Research Institute
Min Zhang: Houston Methodist Research Institute
Bo Xia: Center for Bioinformatics and Computational Biology, Houston Methodist Research Institute
Jie Lv: Center for Bioinformatics and Computational Biology, Houston Methodist Research Institute
Xinlei Gao: Center for Bioinformatics and Computational Biology, Houston Methodist Research Institute
Guangyu Wang: Center for Bioinformatics and Computational Biology, Houston Methodist Research Institute
Qingshu Meng: Northwestern University
Yang Yi: Northwestern University
Sen Zhu: Center for Bioinformatics and Computational Biology, Houston Methodist Research Institute
Alin S. Tomoiaga: The O’Malley School of Business Accounting, Manhattan College
Min Gyu Lee: The University of Texas MD Anderson Cancer Center
John P. Cooke: Houston Methodist Research Institute
Qi Cao: Northwestern University
Kaifu Chen: Center for Bioinformatics and Computational Biology, Houston Methodist Research Institute

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: Abstract Cancers result from a set of genetic and epigenetic alterations. Most known oncogenes were identified by gain-of-function mutations in cancer, yet little is known about their epigenetic features. Through integrative analysis of 11,596 epigenomic profiles and mutations from >8200 tumor-normal pairs, we discover broad genic repression domains (BGRD) on chromatin as an epigenetic signature for oncogenes. A BGRD is a widespread enrichment domain of the repressive histone modification H3K27me3 and is further enriched with multiple other repressive marks including H3K9me3, H3K9me2, and H3K27me2. Further, BGRD displays widespread enrichment of repressed cis-regulatory elements. Shortening of BGRDs is linked to derepression of transcription. BGRDs at oncogenes tend to be conserved across normal cell types. Putative tumor-promoting genes and lncRNAs defined using BGRDs are experimentally verified as required for cancer phenotypes. Therefore, BGRDs play key roles in epigenetic regulation of cancer and provide a direction for mutation-independent discovery of oncogenes.

Date: 2020
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DOI: 10.1038/s41467-020-18913-8

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