A pan-cancer analysis of CpG Island gene regulation reveals extensive plasticity within Polycomb target genes.
A pan-cancer analysis of CpG Island gene regulation reveals extensive plasticity within Polycomb target genes.
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DOI：
10.1038/s41467-021-22720-0
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发表时间：
2021-04-30
影响因子：
16.6
通讯作者：
Berman BP
中科院分区：
文献类型：
--
作者：
Zheng Y;Huang G;Silva TC;Yang Q;Jiang YY;Koeffler HP;Lin DC;Berman BP
CpG岛启动子基因占人类基因的一半以上，并且由多梳抑制复合物2（PRC 2 +-CGI）调控的一个子集在癌症中变得DNA高甲基化和沉默。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PRC 2 +-CGI基因也经常倾向于转录上调。这些上调的PRC 2 +-CGI基因控制着重要的通路，如上皮-间质转化（EMT）和TNFα相关的炎症反应，并且比其他CGI基因具有更高的癌症类型特异性。使用公开的染色质数据集和遗传扰动，我们表明，转录因子结合位点（TFBS）内的远端增强子的PRC 2 +-CGI基因的转录激活的基础，与PRC 2相关的标志H3 K27 me 3在连接的启动子的损失相一致。相比之下，PRC 2-free CGI基因主要由大多数癌症类型常见的启动子TFBS调控。令人惊讶的是，在一种癌症类型中上调的PRC 2 +-CGI基因的大子集在至少一种其他癌症类型中也被高甲基化/沉默，强调了这些基因的高度调节可塑性，可能来源于它们在正常发育期间的复杂调节控制。CpG岛启动子基因的一个子集由多梳抑制复合物2（PRC 2 +-CGI）调节，其在癌症中变得DNA高甲基化并沉默。在这里，作者研究了PRC 2占据的CGI和游离CGI在泛癌症类型中的转录组学和表观基因组学特征。
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. A subset of CpG Island promoter genes are regulated by Polycomb-Repressive Complex 2 (PRC2+-CGI), which become DNA hypermethylated and silenced in cancer. Here, the authors investigate the transcriptomic and epigenomic characteristics of PRC2-occupied CGI and free CGI across pan-cancer types.
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影响因子：
4.6
作者：
Bernhart, Stephan H.;Kretzmer, Helene;Hoffmann, Steve
通讯作者：
Hoffmann, Steve
影响因子：
4.4
作者：
Bibikova, Marina;Barnes, Bret;Shen, Richard
通讯作者：
Shen, Richard
影响因子：
5.2
作者：
Fedele M;Cerchia L;Chiappetta G
通讯作者：
Chiappetta G
影响因子：
11.2
作者：
Hollier BG;Tinnirello AA;Werden SJ;Evans KW;Taube JH;Sarkar TR;Sphyris N;Shariati M;Kumar SV;Battula VL;Herschkowitz JI;Guerra R;Chang JT;Miura N;Rosen JM;Mani SA
通讯作者：
Mani SA
影响因子：
28.2
作者：
Grasso CS;Giannakis M;Wells DK;Hamada T;Mu XJ;Quist M;Nowak JA;Nishihara R;Qian ZR;Inamura K;Morikawa T;Nosho K;Abril-Rodriguez G;Connolly C;Escuin-Ordinas H;Geybels MS;Grady WM;Hsu L;Hu-Lieskovan S;Huyghe JR;Kim YJ;Krystofinski P;Leiserson MDM;Montoya DJ;Nadel BB;Pellegrini M;Pritchard CC;Puig-Saus C;Quist EH;Raphael BJ;Salipante SJ;Shin DS;Shinbrot E;Shirts B;Shukla S;Stanford JL;Sun W;Tsoi J;Upfill-Brown A;Wheeler DA;Wu CJ;Yu M;Zaidi SH;Zaretsky JM;Gabriel SB;Lander ES;Garraway LA;Hudson TJ;Fuchs CS;Ribas A;Ogino S;Peters U
通讯作者：
Peters U