Epigenetic silencing of tumour suppressor gene p15 by its antisense RNA

Nature
Wenqiang YuHengmi Cui

Abstract

Tumour suppressor genes (TSGs) inhibiting normal cellular growth are frequently silenced epigenetically in cancer. DNA methylation is commonly associated with TSG silencing, yet mutations in the DNA methylation initiation and recognition machinery in carcinogenesis are unknown. An intriguing possible mechanism for gene regulation involves widespread non-coding RNAs such as microRNA, Piwi-interacting RNA and antisense RNAs. Widespread sense-antisense transcripts have been systematically identified in mammalian cells, 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. 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. 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 hete...Continue Reading

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