Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Department of Pathology, Shantou University Medical College, Shantou, Guangdong, People's Republic of China.
Nat Commun. 2021 Apr 30;12(1):2485. doi: 10.1038/s41467-021-22720-0.
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.
CpG 岛启动子基因构成了人类基因的一半以上，其中一部分受多梳抑制复合物 2（PRC2-CGI）调控，在癌症中会发生 DNA 超甲基化和沉默。在这里，我们对 TCGA 癌症类型中的 CGI 基因进行了系统分析，发现 PRC2-CGI 基因也经常容易发生转录上调。这些上调的 PRC2-CGI 基因控制着重要的途径，如上皮-间充质转化（EMT）和 TNFα 相关的炎症反应，并且比其他 CGI 基因具有更大的癌症类型特异性。使用公开可用的染色质数据集和遗传扰动，我们表明，远端增强子内的转录因子结合位点（TFBS）是 PRC2-CGI 基因转录激活的基础，同时与连接的启动子上的 PRC2 相关标记 H3K27me3 的丢失一致。相比之下，PRC2 游离的 CGI 基因主要受常见于大多数癌症类型的启动子 TFBS 调控。令人惊讶的是，在一种癌症中上调的 PRC2-CGI 基因的很大一部分在至少另一种癌症中也被超甲基化/沉默，这突显了这些基因的高度调控可塑性，可能源于它们在正常发育过程中的复杂调控控制。
