Periodic Reporting for period 2 - ROPES (ROles of ePitranscriptomic in diseasES)
Periodo di rendicontazione: 2022-12-01 al 2025-05-31
Epitranscriptomics is the study of RNA modifications that regulate gene expression beyond genetic sequences. This rapidly emerging field has great potential to transform our understanding of disease and identify novel therapeutic targets. Modifications such as RNA editing and m6A methylation are crucial, as they link genetic variation to specific cellular behaviours and diseases.
In order to advance Europe’s capabilities in this critical research area, the ROPES project established a pioneering network of Early Stage Researchers (ESRs) to be trained at leading European academic and biotech institutions. ROPES specifically targeted three key disease areas in which epitranscriptomic changes play a significant role: (i) cancer, (ii) stem cell diseases, and (iii) disorders of the innate immune system. These areas were strategically chosen due to their significant societal impact and unmet medical needs.
The project aimed to provide new scientific insights and therapeutic strategies by utilising the latest technological developments in RNA modification analysis. This would address Europe’s competitive disadvantage relative to the US and China in epitranscriptomics research.
In order to advance Europe’s capabilities in this critical research area, the ROPES project established a pioneering network of Early Stage Researchers (ESRs) to be trained at leading European academic and biotech institutions. ROPES specifically targeted three key disease areas in which epitranscriptomic changes play a significant role: (i) cancer, (ii) stem cell diseases, and (iii) disorders of the innate immune system. These areas were strategically chosen due to their significant societal impact and unmet medical needs.
The project aimed to provide new scientific insights and therapeutic strategies by utilising the latest technological developments in RNA modification analysis. This would address Europe’s competitive disadvantage relative to the US and China in epitranscriptomics research.
The ROPES research activities were organised into seven work packages (WPs). Three of these were dedicated to scientific discovery (WPs 1–3), while the others focused on training (WP4), dissemination and communication (WP5), coordination (WP6) and ethics management (WP7).
WP1 developed advanced epitranscriptomic methodologies, bioinformatics tools and databases. Significant outcomes included expanding MODOMICS, a major RNA modification database, and creating NACDDB, a unique nucleic acid circular dichroism database. ROPES researchers also developed innovative site-directed RNA editing techniques that can precisely alter gene expression to study disease mechanisms. Notably, they demonstrated the impact of editing Filamin genes on tumour angiogenesis.
WP2 explored the roles of epitranscriptomics in disease onset and progression. They discovered that changes in m6A RNA methylation significantly influence tumour growth and invasiveness in neuroblastoma, breast cancer, and pancreatic adenocarcinoma. In Drosophila models, m5C methylation enzymes were found to be linked to fertility and neurological phenotypes, and RNA editing mechanisms were identified as being crucial in the regulation of innate immune responses.
The aim of WP3 was to translate epitranscriptomic knowledge into therapeutic concepts. This was successfully achieved by identifying promising small molecules that target m6A reader proteins (YTHDF), RNA editing enzymes (ADAR) and poorly studied RNA modifications, such as N1-methylguanine (m1G). Proof-of-concept studies have demonstrated that modifying RNA interactions can reduce tumour aggressiveness and alter disease-relevant pathways, thus confirming the therapeutic potential of RNA modifications.
WPs 4–7 efficiently delivered training, communication, dissemination, project management and ethical oversight, ensuring that ESRs obtained comprehensive skills in scientific and transferable domains. This led to the awarding of PhDs and future employment in high-profile scientific positions.
WP1 developed advanced epitranscriptomic methodologies, bioinformatics tools and databases. Significant outcomes included expanding MODOMICS, a major RNA modification database, and creating NACDDB, a unique nucleic acid circular dichroism database. ROPES researchers also developed innovative site-directed RNA editing techniques that can precisely alter gene expression to study disease mechanisms. Notably, they demonstrated the impact of editing Filamin genes on tumour angiogenesis.
WP2 explored the roles of epitranscriptomics in disease onset and progression. They discovered that changes in m6A RNA methylation significantly influence tumour growth and invasiveness in neuroblastoma, breast cancer, and pancreatic adenocarcinoma. In Drosophila models, m5C methylation enzymes were found to be linked to fertility and neurological phenotypes, and RNA editing mechanisms were identified as being crucial in the regulation of innate immune responses.
The aim of WP3 was to translate epitranscriptomic knowledge into therapeutic concepts. This was successfully achieved by identifying promising small molecules that target m6A reader proteins (YTHDF), RNA editing enzymes (ADAR) and poorly studied RNA modifications, such as N1-methylguanine (m1G). Proof-of-concept studies have demonstrated that modifying RNA interactions can reduce tumour aggressiveness and alter disease-relevant pathways, thus confirming the therapeutic potential of RNA modifications.
WPs 4–7 efficiently delivered training, communication, dissemination, project management and ethical oversight, ensuring that ESRs obtained comprehensive skills in scientific and transferable domains. This led to the awarding of PhDs and future employment in high-profile scientific positions.
ROPES has significantly strengthened Europe's position in the field of epitranscriptomics by making groundbreaking scientific discoveries and driving technological innovation. The project's research outcomes, published in leading scientific journals, have generated a wealth of fundamental knowledge with direct implications for health and disease management, particularly with regard to difficult-to-treat cancers and immune-related disorders.
The project's creation of new databases and bioinformatics tools has enhanced Europe's capabilities in data-driven RNA research. The successful development of novel editing techniques and therapeutic concepts highlights the potential of epitranscriptomics as a new approach to precision medicine, offering hope for innovative diagnostics and therapies.
By providing rigorous training to Early Stage Researchers (ESRs), ROPES has cultivated a new generation of scientists with the interdisciplinary knowledge required to spearhead Europe's future biomedical research and innovation. This will make a significant contribution to societal well-being and economic competitiveness.
The project's creation of new databases and bioinformatics tools has enhanced Europe's capabilities in data-driven RNA research. The successful development of novel editing techniques and therapeutic concepts highlights the potential of epitranscriptomics as a new approach to precision medicine, offering hope for innovative diagnostics and therapies.
By providing rigorous training to Early Stage Researchers (ESRs), ROPES has cultivated a new generation of scientists with the interdisciplinary knowledge required to spearhead Europe's future biomedical research and innovation. This will make a significant contribution to societal well-being and economic competitiveness.