Epigenetic silencing of tumour suppressor gene p15 by its antisense RNA
Epigenetic silencing of tumour suppressor gene p15 by its antisense RNA
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DOI：
10.1038/nature06468
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发表时间：
2008-01-10
期刊：
影响因子：
64.8
通讯作者：
Cui, Hengmi
中科院分区：
文献类型：
--
作者：
Yu, Wenqiang;Gius, David;Cui, Hengmi
抑制正常细胞生长的肿瘤抑制基因（TSG）在癌症中经常表观遗传学沉默（1）。DNA甲基化通常与TSG沉默相关（1），但致癌过程中DNA甲基化起始和识别机制的突变尚不清楚（2）。一个有趣的可能的基因调控机制涉及广泛的非编码RNA，如microRNA，Piwi相互作用RNA和反义RNA 3 -5。已在哺乳动物细胞中系统地鉴定了广泛的有义-反义转录物（6），并且全局转录组分析显示高达70%的转录物具有反义配偶体，并且反义RNA的扰动可改变有义基因的表达（7）。例如，已经表明，非天然存在但由基因突变诱导的反义转录物导致基因沉默和DNA甲基化，从而导致患者的地中海贫血（8）。在这里，我们表明，许多TSGs附近有反义RNA，我们专注于一个RNA沉默p15，一个细胞周期蛋白依赖性激酶抑制剂牵连白血病的作用。我们发现白血病中p15反义（p15 AS）和p15正义表达之间呈负相关。一个p15 AS表达构建诱导p15沉默的顺式和反式通过异染色质形成，但不DNA甲基化;沉默持续p15 AS关闭后，虽然甲基化和异染色质抑制剂逆转了这一过程。p15 AS诱导的沉默是Dicer非依赖性的。外源性p15 AS在小鼠胚胎干细胞中的表达通过异染色质形成以及胚胎干细胞分化后的DNA甲基化引起p15沉默和生长增加。因此，天然反义RNA可能是肿瘤发生中TSG沉默中异染色质形成和DNA甲基化的触发因素。
Tumour suppressor genes ( TSGs) inhibiting normal cellular growth are frequently silenced epigenetically in cancer(1). DNA methylation is commonly associated with TSG silencing(1), yet mutations in the DNA methylation initiation and recognition machinery in carcinogenesis are unknown(2). An intriguing possible mechanism for gene regulation involves widespread non- coding RNAs such as microRNA, Piwi- interacting RNA and antisense RNAs3-5. Widespread sense - antisense transcripts have been systematically identified in mammalian cells(6), and global transcriptome analysis shows that up to 70% of transcripts have antisense partners and that perturbation of antisense RNA can alter the expression of the sense gene(7). For example, it has been shown that an antisense transcript not naturally occurring but induced by genetic mutation leads to gene silencing and DNA methylation, causing thalassaemia in a patient(8). Here we show that many TSGs have nearby antisense RNAs, and we focus on the role of one RNA in silencing p15, a cyclin- dependent kinase inhibitor implicated in leukaemia. We found an inverse relation between p15 antisense ( p15AS) and p15 sense expression in leukaemia. A p15AS expression construct induced p15 silencing in cis and in trans through heterochromatin formation but not DNA methylation; the silencing persisted after p15AS was turned off, although methylation and heterochromatin inhibitors reversed this process. The p15AS-induced silencing was Dicer- independent. Expression of exogenous p15AS in mouse embryonic stem cells caused p15 silencing and increased growth, through heterochromatin formation, as well as DNA methylation after differentiation of the embryonic stem cells. Thus, natural antisense RNA may be a trigger for heterochromatin formation and DNA methylation in TSG silencing in tumorigenesis.