Binding within or nearby target genes involved in cell proliferation and survival enables the p53 tumor suppressor gene to regulate their transcription and cell-cycle progression. Using genome-wide chromatin-binding profiles, we describe binding of p53 also to regions located distantly from any known p53 target gene. Interestingly, many of these regions possess conserved p53-binding sites and all known hallmarks of enhancer regions. We demonstrate that these p53-bound enhancer regions (p53BERs) indeed contain enhancer activity and interact intrachromosomally with multiple neighboring genes to convey long-distance p53-dependent transcription regulation. Furthermore, p53BERs produce, in a p53-dependent manner, enhancer RNAs (eRNAs) that are required for efficient transcriptional enhancement of interacting target genes and induction of a p53-dependent cell-cycle arrest. Thus, our results ascribe transcription enhancement activity to p53 with the capacity to regulate multiple genes from a single genomic binding site. Moreover, eRNA production from p53BERs is required for efficient p53 transcription enhancement.
Bibliographical noteFunding Information:
We thank Boris Slobodin and Koos Rooijers for technical assistance and the Encode project for providing the publicly available data sets. Further, this work was supported by funds from the European Research Council (ERC), Dutch Cancer Foundation (KWF), Horizon, and Nederlandse Organisatie voor Wetenschappelijk Onderzoek (VICI-NWO) to R.A. and the Fundação para a Ciência e a Tecnologia, Portugal to C.A.M.