Principal Investigator: Maite Huarte Martínez
Funding agency: European Commission – VII Framework Programme
Subsidized by the European Research Council Program - Starting Grant
Mammalian cells encode thousands of RNA molecules structurally similar to protein coding genes –they are large, spliced, poly-adenylated, transcribed by RNA Pol II, with conserved promoters and exonic structures –however lack coding capacity. Although thousands exist, only few of these large intergenic non-coding RNAs (lincRNAs) have been characterized. The few that have show powerful biological roles as regulators of gene expression by diverse epigenetic and non-epigenetic mechanisms. Significantly, their expression patterns suggest that some lincRNAs are involved in cellular pathways critical in cancer, like the p53 pathway. I explored this association demonstrating that p53 induces the expression of many lincRNAs.
One them, named lincRNA-p21, is directly induced by p53 to play a critical role in the p53 response, being required for the global repression of genes that interfere with p53 induction of apoptosis. My results, together with the emerging evidence in the field, suggest that lincRNAs may play key roles in numerous tumor-suppressor and oncogenic pathways, representing an unknown paradigm in cellular transformation. However, their mechanisms of function and biological roles remain largely unexplored.
The goal of this project is to decipher the functional and biological roles of lincRNAs in the context of oncogenic pathways to better understand the cellular mechanisms of gene regulation at the epigenetic and non-epigenetic levels, and be able to implement lincRNA use for diagnostics and therapies. In order to accomplish these goals we will combine molecular and cell biology techniques with functional genomics approaches and in vivo studies. Importantly, the profiling of patient samples will reveal the relevance of our findings in human disease.
Altogether, the functional study of lincRNAs will not only be crucial for developing improved diagnostics and therapies, but also will help to a better understanding of the mechanisms that govern cellular networks.
Non-coding RNA (ncRNA) is a new research field in rapid development. It holds the potential to explain many fundamental biological phenomena and there is a vast prospective for the development of ncRNA-derived diagnostic and therapeutic tools. Hence, biotech and pharmaceutical companies are actively looking into this unexplored territory for novel targets. Therefore, there is a substantial and unmet need for the training of scientists in ncRNA biology, methodology and exploitation.
The regions encompassing protein coding potential (exons) in humans only amount to 2% of the genome. New sequencing techniques have evidenced that mammalian genomes are pervasively transcribed and have revealed the existence of multiple classes of ncRNAs. Although our knowledge on the multitude of transcripts produced by the non-coding 98% of the genome is still very sketchy, pivotal roles have been established for ncRNAs in organismal development and homeostasis, in cellular proliferation, differentiation and apoptosis and in a broad range of human pathologies.
Hence, there is a need to educate young scientists in this emerging and important research field. Aside from increasing our collective understanding of essential biological phenomena, ncRNA also constitute a vast and largely unexplored territory for the development of novel therapeutics and diagnostics.
Accordingly, we propose to form a European RNA training network, RNATRAIN. This network will be devoted to educating the next generation of European researchers focusing on the functions and importance of ncRNAs in multidisciplinary projects in which the ncRNAs are studied in the context of development, differentiation and disease. Towards this, a group of 9 top-quality European research laboratories and 2 companies from 8 countries will train, to the best level, a cohort of early-stage researchers using cutting-edge technologies to dissect the functions and potentials of ncRNAs through integrated multidisciplinary projects.
University of Copenhagen The Netherlands Cancer Institute Max-Delbrück-Center for Molecular Medicine
Gothenburg University Institute of Molecular Genetics of the ASCR University of Basel
Universita Degli Studi di Roma la Sapienza University of Regensburg Intana Bioscience GmbH