RNA modifications are beginning to define a novel layer of biological complexity that is becoming widely appreciated as the epitranscriptome. To date over 170 known chemical modifications are known in RNA and emerging evidence is revealing that post-transcriptional modifications mediate regulation of gene expression and protein translation efficiency and accuracy. Our main interest is to decipher novel epitranscriptomic mechanisms affecting human disorders, with special focus on cancer and other degenerative diseases. We seek to understand how RNA modifications regulate self-renewal, differentiation, growth, survival and invasion processes in normal and malignant cells.
To this aim, we combine state-of-the-art transcriptome-wide sequencing methods, with biochemical methods, mouse models, human cancer cell lines, stem cell cultures, patient samples and 3D culture models to study the role of post-transcriptional modifications such as RNA methylation in tissue and cancer stem cell functions, development and cancer initiation, progression, metastasis and therapy tolerance development.
1 – We have shown that RNA modifications are novel regulators of gene expression at the protein synthesis level, which in turn regulate cellular processes. In particular we have shown that m5C on transfer RNA (tRNAs) can regulate their processing into small non coding RNAs (ncRNAs)-derived tRNA fragments, which in turn regulate the translation machinery favouring the expression of stress response and migration genes, and thus regulating those processes in tissue homeostasis and disease. m5C dynamic deposition is fundamental for metabolic regulation and cell cycle progression. Now we aim to characterize the role of RNA modifications, “writers”, “erasers” and “protein readers” in the regulation of tissue homeostasis in normal development. Characterize their functional role in cellular processes including proliferation, self-renewal, differentiation, migration or adaptation to microenvironment changes or stress stimuli.
2 – Emerging evidence implicates a key role for non-mutational stress resistance mechanisms such as epigenetics and epitranscriptomics underlying the survival of residual cancer cells. Unlike DNA epigenetics with only one major chemical modification known, over 170 chemical modifications of RNA are known to compose “the epitranscriptome”. Their function remains still widely unknown, however they are emerging as modulators of self-renewal, differentiation, stress responses and their alterations are associated to cancer. Now we aim to identify the epitranscriptome in disease and determine the impact of aberrant deposition in cancer and in neurodegenerative diseases. Define and characterize genomic or transcriptional alterations of RNA modifying enzymes including “writers”, “erasers” and “protein readers” in several tumour types.
3 – Cancer is a highly heterogeneous and dynamic disease that arises from the integrated dysregulation of different cellular processes including metastasis or immunity responses. The information regarding the connection between the epitranscriptome and tumour microenvironment (MEV), epithelial–mesenchymal transition (EMT), metastasis or cancer immune-suppressive regulation is limited, however recent data suggest that could be an interesting target for the treatment of tumours. The recent observations require the detailed exploration of the mechanism by which metastasis and cancer immune-suppressive activity are regulated by RNA modifying proteins and the therapeutic potential.Thus our objective is to identify critical RNA modifying proteins that regulate the crosstalk of tumour cells with the micro-environment to find therapeutical strategies to influence metastasis or cancer-associated immune responses.
4 – The fast evolving knowledge we have acquired on the role of the epitranscriptome in homeostasis and diseases is mainly due to our current capacity of detecting RNA modifications at single nucleotide resolution. To date few RNA modifications are being explore mainly due to the lack of high throughput detection methods that allow us the identification of novel modifications. Thus we aim to develop novel high throughput RNA modifications detection methods to then discover the epitranscriptomic landscape in health and disease.
5 – Discovering the molecular function of modified RNAs are key to understand their role in physiology and pathology. We aim to determine the fate of RNA modified RNAs applying RNA sequencing, proteomic and microscopy approaches.
6 – Determine the therapeutic potential of the manipulation of the epitranscriptome in cancer cells. Development of small molecule inhibitors of RNA modifying enzymes that are altered in cancer.