Objective Enhancers are genomic domains that regulate transcription of distantly located genes and that are characterized by specific chromatin signatures of histone methylation and acetylation patterns. Interestingly, RNA polymerase II (RNAPII) binds to a subset of enhancers and produces transcripts, called enhancer RNAs (eRNAs). These are produced bi-directionally and, in contrast to mRNAs and many other non-coding RNAs, are not polyadenylated. Generally, the transcription of eRNAs was shown to positively correlate with mRNA levels of surrounding protein-coding genes. However, it is unclear if eRNAs carry a transcriptional function.p53 is a transcription factor and tumor suppressor that is very frequently mutated in cancer. Chromatin-binding profiles reveal specific interactions of p53 with promoter regions of nearby genes, within genes, but also with remote regions located more than 50 kbps away from any known gene. Interestingly, many of these remote regions possess evolutionary highly conserved p53-binding sites and all known hallmarks of enhancer regions, as well as binding of RNAPII. We found out that many remote p53-bound domains are indeed p53-dependent eRNA-producing enhancers, and, most importantly, eRNA production was required for transcriptional induction of distal genes and for p53-dependent cellular control.Here we will:1. Investigate in detail the mechanism of action and function of p53-dependent eRNAs.2. Expand studies to identify eRNAs with oncogenic function.3. Develop efficient ways to target eRNAs.4. Target eRNAs and study their capacity to inhibit tumorigenicity.As eRNAs are mediators of enhancer activity with sequence specific content and sensitivity to siRNA targeting, they might be the Achilles heel through which oncogenic enhancer activity could be suppressed. Our study will elucidate a novel layer of gene regulation and holds promise for opening up new opportunities to affect cancer-related cellular programs in very specific and effectiv Fields of science medical and health sciencesclinical medicineoncologynatural sciencesbiological sciencesgeneticsRNA Programme(s) FP7-IDEAS-ERC - Specific programme: "Ideas" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013) Topic(s) ERC-AG-LS2 - ERC Advanced Grant - Genetics, Genomics, Bioinformatics and Systems Biology Call for proposal ERC-2012-ADG_20120314 See other projects for this call Funding Scheme ERC-AG - ERC Advanced Grant Host institution STICHTING HET NEDERLANDS KANKER INSTITUUT-ANTONI VAN LEEUWENHOEK ZIEKENHUIS EU contribution € 2 176 840,00 Address PLESMANLAAN 121 1066 CX Amsterdam Netherlands See on map Region West-Nederland Noord-Holland Groot-Amsterdam Activity type Research Organisations Administrative Contact Henri Van Luenen (Dr.) Principal investigator Reuven Agami (Prof.) Links Contact the organisation Opens in new window Website Opens in new window Total cost No data Beneficiaries (1) Sort alphabetically Sort by EU Contribution Expand all Collapse all STICHTING HET NEDERLANDS KANKER INSTITUUT-ANTONI VAN LEEUWENHOEK ZIEKENHUIS Netherlands EU contribution € 2 176 840,00 Address PLESMANLAAN 121 1066 CX Amsterdam See on map Region West-Nederland Noord-Holland Groot-Amsterdam Activity type Research Organisations Administrative Contact Henri Van Luenen (Dr.) Principal investigator Reuven Agami (Prof.) Links Contact the organisation Opens in new window Website Opens in new window Total cost No data