p53 binds enhancers to regulate key target genes. Here, we globally mapped p53-regulated enhancers by looking at enhancer RNA (eRNA) production. Intriguingly, while many p53-induced enhancers contained p53-binding sites, most did not. As long non-coding RNAs (lncRNAs) are prominent regulators of chromatin dynamics, we hypothesized that p53-induced lncRNAs contribute to the activation of enhancers by p53. Among p53-induced lncRNAs, we identified LED and demonstrate that its suppression attenuates p53 function. Chromatin-binding and eRNA expression analyses show that LED associates with and activates strong enhancers. One prominent target of LED was located at an enhancer region within CDKN1A gene, a potent p53-responsive cell cycle inhibitor. LED knockdown reduces CDKN1A enhancer induction and activity, and cell cycle arrest following p53 activation. Finally, promoter-associated hypermethylation analysis shows silencing of LED in human tumours. Thus, our study identifies a new layer of complexity in the p53 pathway and suggests its dysregulation in cancer.
Sample name | Organism | Experiment title | Sample type | Library instrument | Attributes | |||||||||||||||||||||||||||||||||||||||||||||||||
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cell line | chirp pool probe sequences | source name | ||||||||||||||||||||||||||||||||||||||||||||||||||||
MCF7 GROseq nutlin 2 | Homo sapiens | GSM1422218: MCF7 GROseq nutlin 2; Homo sapiens; OTHER | OTHER | Illumina HiSeq 2000 | MCF7 | mammary gland/breast | ||||||||||||||||||||||||||||||||||||||||||||||||
MCF7 GROseq nutlin 1 | Homo sapiens | GSM1422217: MCF7 GROseq nutlin 1; Homo sapiens; OTHER | OTHER | Illumina HiSeq 2000 | MCF7 | mammary gland/breast | ||||||||||||||||||||||||||||||||||||||||||||||||
MCF7 GROseq control 2 | Homo sapiens | GSM1422216: MCF7 GROseq control 2; Homo sapiens; OTHER | OTHER | Illumina HiSeq 2000 | MCF7 | mammary gland/breast | ||||||||||||||||||||||||||||||||||||||||||||||||
MCF7 GROseq control 1 | Homo sapiens | GSM1422215: MCF7 GROseq control 1; Homo sapiens; OTHER | OTHER | Illumina HiSeq 2000 | MCF7 | mammary gland/breast | ||||||||||||||||||||||||||||||||||||||||||||||||
MCF7 p21ekd siep21e 2 | Homo sapiens | GSM1294988: MCF7 p21ekd siep21e 2; Homo sapiens; RNA-Seq | RNA-Seq | Illumina HiSeq 2000 | MCF7 | mammary gland/breast |