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A pan-cancer analysis of CpG Island gene regulation reveals extensive plasticity within Polycomb target genes

Author

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  • Yueyuan Zheng

    (Cedars-Sinai Medical Center)

  • Guowei Huang

    (Cedars-Sinai Medical Center
    Shantou University Medical College)

  • Tiago C. Silva

    (Cedars-Sinai Medical Center)

  • Qian Yang

    (Cedars-Sinai Medical Center)

  • Yan-Yi Jiang

    (Cedars-Sinai Medical Center)

  • H. Phillip Koeffler

    (Cedars-Sinai Medical Center)

  • De-Chen Lin

    (Cedars-Sinai Medical Center)

  • Benjamin P. Berman

    (Hebrew University-Hadassah Medical School)

Abstract

CpG Island promoter genes make up more than half of human genes, and a subset regulated by Polycomb-Repressive Complex 2 (PRC2+-CGI) become DNA hypermethylated and silenced in cancer. Here, we perform a systematic analysis of CGI genes across TCGA cancer types, finding that PRC2+-CGI genes are frequently prone to transcriptional upregulation as well. These upregulated PRC2+-CGI genes control important pathways such as Epithelial-Mesenchymal Transition (EMT) and TNFα-associated inflammatory response, and have greater cancer-type specificity than other CGI genes. Using publicly available chromatin datasets and genetic perturbations, we show that transcription factor binding sites (TFBSs) within distal enhancers underlie transcriptional activation of PRC2+-CGI genes, coinciding with loss of the PRC2-associated mark H3K27me3 at the linked promoter. In contrast, PRC2-free CGI genes are predominantly regulated by promoter TFBSs which are common to most cancer types. Surprisingly, a large subset of PRC2+-CGI genes that are upregulated in one cancer type are also hypermethylated/silenced in at least one other cancer type, underscoring the high degree of regulatory plasticity of these genes, likely derived from their complex regulatory control during normal development.

Suggested Citation

  • Yueyuan Zheng & Guowei Huang & Tiago C. Silva & Qian Yang & Yan-Yi Jiang & H. Phillip Koeffler & De-Chen Lin & Benjamin P. Berman, 2021. "A pan-cancer analysis of CpG Island gene regulation reveals extensive plasticity within Polycomb target genes," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-22720-0
    DOI: 10.1038/s41467-021-22720-0
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