Table_5_A Class of Protein-Coding RNAs Binds to Polycomb Repressive Complex 2 and Alters Histone Methylation.xlsx

Polycomb repressive complex 2 (PRC2) is a multi-subunit protein complex mediating the methylation of lysine 27 on histone H3 and playing an important role in transcriptional repression during tumorigenesis and development. Previous studies revealed that both protein-coding and non-coding RNAs could bind to PRC2 complex. However, the functions of protein-coding RNAs that bind to PRC2 complex in tumor are still unknown. Through data mining and RNA immunoprecipitation (RIP) assay, our study found that there were a class of protein-coding RNAs bound to PRC2 complex and H3 with tri-methylation on lysine 27. The Bayesian gene regulatory network analysis pointed out that these RNAs regulated the expression of PRC2-regulated genes in cancer. In addition, gene set enrichment analysis (GSEA), gene ontology (GO) analysis, and weighted gene co-expression network analysis (WGCNA) also confirmed that these RNAs were associated with histone modification in cancer. We also confirmed that MYO1C, a PRC2-bound transcript, inhibited the modification level of H3K27me3. Further detailed study showed that TMEM117 regulated TSLP expression through EZH2-mediated H3K27me3 modification. Interestingly, the RNA recognition motif of PRC2 complex might help these RNAs bind to the PRC2 complex more easily. The same regulatory pattern was found in mice as well.

多梳抑制复合体2（Polycomb repressive complex 2, PRC2）是一种多亚基蛋白质复合体，可介导组蛋白H3赖氨酸27位点的甲基化修饰，并在肿瘤发生与发育过程中对转录抑制发挥重要作用。既往研究表明，编码RNA与非编码RNA均可结合PRC2复合体。然而，肿瘤中结合PRC2复合体的编码RNA的功能仍未明确。本研究通过数据挖掘与RNA免疫沉淀试验（RNA immunoprecipitation, RIP），发现存在一类可同时结合PRC2复合体与赖氨酸27三甲基化修饰H3的编码RNA。贝叶斯基因调控网络分析显示，这类RNA可在癌症中调控PRC2靶基因的表达。此外，基因集富集分析（gene set enrichment analysis, GSEA）、基因本体（gene ontology, GO）分析与加权基因共表达网络分析（weighted gene co-expression network analysis, WGCNA）也证实，这类RNA与癌症中的组蛋白修饰密切相关。本研究还证实，MYO1C作为一种结合PRC2的转录本，可抑制H3K27me3的修饰水平。进一步的详细研究显示，TMEM117可通过EZH2介导的H3K27me3修饰调控TSLP的表达。有趣的是，PRC2复合体的RNA识别基序或许可帮助这类RNA更轻松地结合PRC2复合体。该调控模式在小鼠体内也得到了验证。