Periodic Reporting for period 1 - ROPES (ROles of ePitranscriptomic in diseasES)
Berichtszeitraum: 2020-12-01 bis 2022-11-30
ROPES will establish a competitive network of Early Stage Researchers (ESRs) recruited and trained to join European academic research groups and biotech companies with the common goal of advancing our knowledge on the role of RNA modifications in a broad spectrum of disease states to provide ground for the identification of new therapies.
This objective will be achieved by investigating mostly the two major, and best studied, forms of mRNA modifications, RNA editing and m6A methylation.
Starting from the RNA editing and m6A methylation established physiological functions, ROPES has selected three disease domains in which to investigate disease mechanisms and look for new therapies: (i) cancer; (ii) stem cell diseases; (iii) innate immunity.The first two broad domains are all related to the program of clonal expansion of stem cell populations - in other words, the interplay between symmetric and asymmetric cell division - since cancer can also be considered a stem cell disease with alteration in this interplay.
The emerging field of epitranscriptomics is crucial for both basic science and application to human disease. Epitranscriptomic would provide the missing link between genomic variability and cellular phenotypes, contributing to explaining the cause of specific diseases and developing novel therapies.
Epitranscriptomic research is dominated by the US and China, with the EU lagging behind. The ROPES European Training Network is the first European effort to tackle the epitranscriptome for the advancement of medicine.
This objective will be achieved by investigating mostly the two major, and best studied, forms of mRNA modifications, RNA editing and m6A methylation.
Starting from the RNA editing and m6A methylation established physiological functions, ROPES has selected three disease domains in which to investigate disease mechanisms and look for new therapies: (i) cancer; (ii) stem cell diseases; (iii) innate immunity.The first two broad domains are all related to the program of clonal expansion of stem cell populations - in other words, the interplay between symmetric and asymmetric cell division - since cancer can also be considered a stem cell disease with alteration in this interplay.
The emerging field of epitranscriptomics is crucial for both basic science and application to human disease. Epitranscriptomic would provide the missing link between genomic variability and cellular phenotypes, contributing to explaining the cause of specific diseases and developing novel therapies.
Epitranscriptomic research is dominated by the US and China, with the EU lagging behind. The ROPES European Training Network is the first European effort to tackle the epitranscriptome for the advancement of medicine.
ROPES project divides its activity into 7 WPs. WP1-3 are dedicated to scientific tasks, while WP4-7 deal with training, dissemination, exploitation, communication, management and ethical issues.
WP1 aims at extending the tools of epitranscriptomics to fight diseases. Epitranscriptomic datasets in this WP are being curated and integrated into easy-to-use resources that can support such analyses. ROPES is employing the latest techniques in computational biology, biochemistry, and high-throughput sequencing to advance our capabilities in exploiting the epitranscriptome to understand and contrast diseases. ESR2 (MUW) has established methods to specifically introduce site-directed RNA editing by ADARs to determine the impact of individual adenosine deamination events on a) other RNA modifications and b) cellular properties. ESR4 (IIMCB) developed and edited MODOMICS and developed a new database for the study of circular dichroism spectra applied to nucleic acids, published on NAR. ESR6 (DKFZ) asked the question how 5-methylcytosine in tRNAs regulates the formation of new blood vessels in vivo.The objective of ESR7’s project (CNR) is to exploit programmable RNA editing to trigger cell death through synthetic lethality. ESR8 (CRG) has made significant progress in the establishment of single cell direct RNA nanopore sequencing. ESR10 (IMMAGINA) is developing a new Ribo-Seq method based on Direct RNA sequencing using Oxford Nanopore Technologies (ONT). ESR12 has first identified the most appropriate input data to develop his algorithm, selecting the eCLIP assay and has applied several unsupervised learning techniques to identify clusters of RBP pairs.WP2 deals with two broad classes of disease states cell proliferation imbalances and innate immunity alterations. WP2 aims to improve our understanding of how epitranscriptomic marks and their aberrations influence the onset and the progression of these fundamental disease classes by molecular and developmental biology approaches. ESR1 (UNITN) has contributed to the evaluation of the role of m6A genes in the behaviour of the pediatric tumor neuroblastoma. ESR2 (MUW) could demonstrate that structured RNAs that are bound by the innate immune sensor MDA5 in the absence of ADARs can stimulate interferon signalling when transfected into cells. ESR3 (UNIL) has been working on the role of Nsun7 ortholog CG44836 in Drosophila melanogaster. The work developed by ESR5 (UMEA) has been focused on how cytoplasmic METTL3 influences breast cancer tumorigenesis. ESR9 (CEITEC-MU) has focused on the role of ADAR in innate immunity in Drosophila.WP3 aims to understand how the activity of individual proteins can be modulated by small molecules, or employing tools to affect specific epitranscriptomic decorations on selected RNAs that will thus offer a way to exploit epitranscriptomics to address disease states. WP3 therefore employs cutting-edge techniques to demonstrate proof-of-concept approaches to modify the lifecycle of epitranscriptomic effectors and marks as therapeutic strategies in various diseases. ESR1 (UNITN) has worked towards assessing the potential of small molecule inhibitors of the binding between YTHDF proteins and the m6A modification. The main objective for ESR10 (IMMAGINA) in this WP was to develop a bioinformatics pipeline to integrate RNA editing signatures with parallel classical Ribo-seq and RNA-seq data. ESR10 started to write a bioinformatics package named MARTIAN (‘MrnAs at Ribosomes and Trna Included Analyzer’) to integrate RNA and ribosome features resulting from Ribo-seq, RNA-seq, and tRNA-seq. The objective of ERS11 (ULB) is to identify and understand the function of a poorly studied RNA modification, N1-methylguanine (m1G) and its role in cancer.
WP4, WP5, WP6 and wp7 are progressing correctly and adequately according to the DoA.
WP1 aims at extending the tools of epitranscriptomics to fight diseases. Epitranscriptomic datasets in this WP are being curated and integrated into easy-to-use resources that can support such analyses. ROPES is employing the latest techniques in computational biology, biochemistry, and high-throughput sequencing to advance our capabilities in exploiting the epitranscriptome to understand and contrast diseases. ESR2 (MUW) has established methods to specifically introduce site-directed RNA editing by ADARs to determine the impact of individual adenosine deamination events on a) other RNA modifications and b) cellular properties. ESR4 (IIMCB) developed and edited MODOMICS and developed a new database for the study of circular dichroism spectra applied to nucleic acids, published on NAR. ESR6 (DKFZ) asked the question how 5-methylcytosine in tRNAs regulates the formation of new blood vessels in vivo.The objective of ESR7’s project (CNR) is to exploit programmable RNA editing to trigger cell death through synthetic lethality. ESR8 (CRG) has made significant progress in the establishment of single cell direct RNA nanopore sequencing. ESR10 (IMMAGINA) is developing a new Ribo-Seq method based on Direct RNA sequencing using Oxford Nanopore Technologies (ONT). ESR12 has first identified the most appropriate input data to develop his algorithm, selecting the eCLIP assay and has applied several unsupervised learning techniques to identify clusters of RBP pairs.WP2 deals with two broad classes of disease states cell proliferation imbalances and innate immunity alterations. WP2 aims to improve our understanding of how epitranscriptomic marks and their aberrations influence the onset and the progression of these fundamental disease classes by molecular and developmental biology approaches. ESR1 (UNITN) has contributed to the evaluation of the role of m6A genes in the behaviour of the pediatric tumor neuroblastoma. ESR2 (MUW) could demonstrate that structured RNAs that are bound by the innate immune sensor MDA5 in the absence of ADARs can stimulate interferon signalling when transfected into cells. ESR3 (UNIL) has been working on the role of Nsun7 ortholog CG44836 in Drosophila melanogaster. The work developed by ESR5 (UMEA) has been focused on how cytoplasmic METTL3 influences breast cancer tumorigenesis. ESR9 (CEITEC-MU) has focused on the role of ADAR in innate immunity in Drosophila.WP3 aims to understand how the activity of individual proteins can be modulated by small molecules, or employing tools to affect specific epitranscriptomic decorations on selected RNAs that will thus offer a way to exploit epitranscriptomics to address disease states. WP3 therefore employs cutting-edge techniques to demonstrate proof-of-concept approaches to modify the lifecycle of epitranscriptomic effectors and marks as therapeutic strategies in various diseases. ESR1 (UNITN) has worked towards assessing the potential of small molecule inhibitors of the binding between YTHDF proteins and the m6A modification. The main objective for ESR10 (IMMAGINA) in this WP was to develop a bioinformatics pipeline to integrate RNA editing signatures with parallel classical Ribo-seq and RNA-seq data. ESR10 started to write a bioinformatics package named MARTIAN (‘MrnAs at Ribosomes and Trna Included Analyzer’) to integrate RNA and ribosome features resulting from Ribo-seq, RNA-seq, and tRNA-seq. The objective of ERS11 (ULB) is to identify and understand the function of a poorly studied RNA modification, N1-methylguanine (m1G) and its role in cancer.
WP4, WP5, WP6 and wp7 are progressing correctly and adequately according to the DoA.
The ROPES network is facilitate the building of a critical mass of European scientists devoted to studying epitranscriptomics. The topics addressed by the research and training program of the network are contribute to our understanding and ability to exploit epitranscriptomics towards new therapeutic strategies for diseases (e.g. cancer) that represent an area of considerable social impact in the EU.
Topics and techniques employed are at the forefront of the field, with an entire WP devoted to technological improvement. This highly technological aspect will be fundamental in improving our ability to understand the role of RNA modifications in human health and disease. The work done at the consortium is contributing to answer questions that are at the frontier of our knowledge in this field, exploring the potential for RNA modifications to be highly specific and effective drug targets for still untreatable diseases such as neuroblastoma and pancreatic cancer. The shared approach of the network proposes that the regulation of RNA modifications may beparticularly relevant to substantially ameliorate the cause of socially-impacting health problems. Accordingly ROPES is realizing twelve research project that promise to deliver major advances in basic and translational research that can improve our knowledge of the mechanisms of modulating disease development.
Addressing this challenge the outcomes of the project may impact the EU economy and society: a) realizing the increased competitiveness of novel European scientists in the field of epitranscriptomics; b) delivering important technological developments that will assist the study of epitranscriptomics and ensuring further discoveries; c) promoting an multidisciplinary effort to address new research and medical challenges that may be translated into business opportunities by generating new intellectual property. In terms of public health, beyond its conclusion, the impact of the project will be to favour the development of innovative diagnostic and therapeutic solutions
Topics and techniques employed are at the forefront of the field, with an entire WP devoted to technological improvement. This highly technological aspect will be fundamental in improving our ability to understand the role of RNA modifications in human health and disease. The work done at the consortium is contributing to answer questions that are at the frontier of our knowledge in this field, exploring the potential for RNA modifications to be highly specific and effective drug targets for still untreatable diseases such as neuroblastoma and pancreatic cancer. The shared approach of the network proposes that the regulation of RNA modifications may beparticularly relevant to substantially ameliorate the cause of socially-impacting health problems. Accordingly ROPES is realizing twelve research project that promise to deliver major advances in basic and translational research that can improve our knowledge of the mechanisms of modulating disease development.
Addressing this challenge the outcomes of the project may impact the EU economy and society: a) realizing the increased competitiveness of novel European scientists in the field of epitranscriptomics; b) delivering important technological developments that will assist the study of epitranscriptomics and ensuring further discoveries; c) promoting an multidisciplinary effort to address new research and medical challenges that may be translated into business opportunities by generating new intellectual property. In terms of public health, beyond its conclusion, the impact of the project will be to favour the development of innovative diagnostic and therapeutic solutions