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Broad genic repression domains signify enhanced silencing of oncogenes

Dongyu Zhao1,2,3,4, Lili Zhang5,6,7, Min Zhang2,3,4

  • 1Center for Bioinformatics and Computational Biology, Houston Methodist Research Institute, Houston, TX, USA.

Nature Communications
|November 4, 2020
PubMed

Insights

Researchers discovered broad genic repression domains (BGRDs) as a new epigenetic signature for oncogenes. These domains, marked by repressive histone modifications, help identify cancer-driving genes independently of mutations.

Area of Science:

  • Cancer Biology
  • Epigenetics
  • Genomics

Background:

  • Cancers arise from genetic and epigenetic changes.
  • Oncogenes are typically identified by gain-of-function mutations.
  • Epigenetic features of oncogenes remain largely unexplored.

Purpose of the Study:

  • To identify novel epigenetic signatures associated with oncogenes.
  • To explore the role of chromatin modifications in cancer development.
  • To develop mutation-independent methods for oncogene discovery.

Main Methods:

  • Integrative analysis of 11,596 epigenomic profiles and >8200 tumor-normal mutation pairs.
  • Characterization of broad genic repression domains (BGRDs) using histone modification data (H3K27me3, H3K9me3, H3K9me2, H3K27me2).
  • Analysis of cis-regulatory element enrichment and BGRD length correlation with gene transcription.

Main Results:

  • Discovery of broad genic repression domains (BGRDs) as an epigenetic signature for oncogenes.
  • BGRDs are characterized by widespread enrichment of repressive histone marks (H3K27me3, H3K9me3, etc.) and repressed cis-regulatory elements.
  • Shortening of BGRDs correlates with gene derepression, and BGRDs at oncogenes are conserved in normal cells.
  • Putative oncogenes and lncRNAs identified via BGRDs were experimentally validated as crucial for cancer phenotypes.

Conclusions:

  • Broad genic repression domains (BGRDs) are key epigenetic regulators in cancer.
  • BGRDs offer a novel, mutation-independent strategy for identifying oncogenes.
  • This discovery advances our understanding of epigenetic mechanisms in cancer and oncogene identification.

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