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.
Highlights
Cancers result from a set of genetic and epigenetic alterations
We describe the discovery of broad genic repression domains (BGRD), defined by widespread H3K27me[3] modification, as an epigenetic signature to provide mutationindependent information for discovery of oncogenes
Defined in CD4+ T cells, BGRD genes were not enriched in T cell pathways, but were enriched in the Pathways In Cancer (KEGG entry ID hsa05200) (Fig. 1f), a set of 330 cancer genes manually curated from literature[20]
Summary
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. H3K27me[3] is a hallmark of heterochromatin It is not completely clear how it functions in gene repression[3]. We describe the discovery of broad genic repression domains (BGRD), defined by widespread H3K27me[3] modification, as an epigenetic signature to provide mutationindependent information for discovery of oncogenes. We illustrate how this signature is linked to gene structure and the composition of cis-regulatory elements. We subsequently utilize the BGRD signature to identify oncogenes, as well as oncogenic lncRNAs followed by comprehensive verifications
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