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

Yueyuan Zheng, Guowei Huang, Tiago C. Silva, Qian Yang, Yan-Yi Jiang, H. Phillip Koeffler, Lin De-Chen () and Benjamin P. Berman ()
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Yueyuan Zheng: Cedars-Sinai Medical Center
Guowei Huang: Cedars-Sinai Medical Center
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
Lin De-Chen: Cedars-Sinai Medical Center
Benjamin P. Berman: Hebrew University-Hadassah Medical School

Nature Communications, 2021, vol. 12, issue 1, 1-16

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-22720-0

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