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Projects / Programmes source: ARIS

Post-transcriptional regulatory networks in neurodegenerative diseases.

Research activity

Code Science Field Subfield
1.05.00  Natural sciences and mathematics  Biochemistry and molecular biology   

Code Science Field
B110  Biomedical sciences  Bioinformatics, medical informatics, biomathematics biometrics 

Code Science Field
1.06  Natural Sciences  Biological sciences 
Keywords
protein-RNA interactions, iCLIP, alternative splicing, 3’ end processing, post-transcriptional regulation, RNA maps, splicing code, high-throughput sequencing, bioinformatics, data mining, data integration
Evaluation (rules)
source: COBISS
Researchers (20)
no. Code Name and surname Research area Role Period No. of publicationsNo. of publications
1.  22482  MSc Goran Bobojević  Computer science and informatics  Researcher  2014 - 2015  12 
2.  23399  PhD Tomaž Curk  Computer science and informatics  Researcher  2013 - 2016  253 
3.  16324  PhD Janez Demšar  Computer science and informatics  Researcher  2013 - 2016  340 
4.  32930  Aleš Erjavec    Technical associate  2016  12 
5.  30697  PhD Anja Kovanda  Neurobiology  Researcher  2013 - 2014  74 
6.  36139  Adviti Naik  Computer science and informatics  Researcher  2013 
7.  30710  PhD Sonja Prpar Mihevc  Neurobiology  Researcher  2014 - 2016  108 
8.  30887  PhD Anja Pucer Janež  Pharmacy  Researcher  2014 - 2015  58 
9.  15813  PhD Boris Rogelj  Neurobiology  Researcher  2013 - 2016  410 
10.  33189  Anže Starič  Computer science and informatics  Junior researcher  2013 - 2014 
11.  37827  PhD Martin Stražar  Computer science and informatics  Researcher  2015  35 
12.  33328  PhD Maja Štalekar  Biochemistry and molecular biology  Junior researcher  2013 - 2014  49 
13.  30142  PhD Marko Toplak  Computer science and informatics  Researcher  2013 - 2016  27 
14.  34667  PhD Jernej Ule  Biochemistry and molecular biology  Head  2013 - 2016  178 
15.  35506  PhD Sabina Vatovec  Biology  Researcher  2014  28 
16.  37693  MSc Maja Vodopivec  Computer science and informatics  Researcher  2014 - 2016 
17.  12536  PhD Blaž Zupan  Computer science and informatics  Researcher  2013 - 2016  530 
18.  30921  PhD Lan Žagar  Computer science and informatics  Researcher  2013 - 2014  17 
19.  32929  Jure Žbontar  Computer science and informatics  Researcher  2015 
20.  17285  Darja Žunič Kotar    Technical associate  2013 - 2016 
Organisations (2)
no. Code Research organisation City Registration number No. of publicationsNo. of publications
1.  0106  Jožef Stefan Institute  Ljubljana  5051606000  89,948 
2.  1539  University of Ljubljana, Faculty of Computer and Information Science  Ljubljana  1627023  15,991 
Abstract
The recent years have seen an explosion of new methods employing high-throughput sequencing (HTS) to understand the functions of RNA-binding proteins (RBPs). The resulting data requires customized computational tools for its interpretation. Here we propose to develop such tools, with the overarching goal to increase the understanding of the mechanistic principles underlying RNA-dependent regulation of gene expression. Therefore, we aim to drive forward the research in bioinformatics, and provide the tools required by the experimental scientists to study the systems biology of RNA.   The project will develop new data mining and artificial intelligence tools, and embed them into an intelligent web-based assistant for explorative analysis of these data. These tools will significantly advance the data-intensive computational studies of protein-RNA interactions and gene expression. Importantly, these tools will be capable of deriving new hypotheses, which will serve as a starting point for further experiments in the Ule group, aimed at understanding how the defects in the regulatory mechanisms contribute to neurodegenerative diseases. Specifically, we will achieve the following (objectives):   1)   Build a computational pipeline to map, quantify and visualize the protein-RNA interactions and model the post-transcriptional regulation of gene expression. 2)   Develop a new descriptive language and efficient heuristics to integrate and model the relations among different post-transcriptional regulatory stages and infer new hypotheses explaining the molecular functions of RNA binding proteins and global mechanistic regulatory patterns. 3)   Infer predictive models through machine learning and implement an intelligent, web-based interface for explorative analysis that will direct the researcher to the critical regulatory sites and will reveal the regulatory mechanisms unique to each protein. 4)   Integrate the data of state-of-the-art high-throughput sequencing methods in order to dissect the molecular mechanisms of the two RBPs associated with neurodegenerative diseases: TDP-43 and FUS.   The Zupan group (FRI), University of Ljubljana, Faculty of Computer and Information Science, Ljubljana, Slovenia has a proven track record in the analysis and visualization of next-generation sequencing data, machine learning and software development. Members of the Zupan group will be working closely together with members of the Ule group (LMB), MRC Laboratory of Molecular Biology, Cambridge, UK, which are developing new experimental methods and have expertise in genomics and studies of protein-RNA interactions. Both groups will collaborate with Rogelj group (IJS), Jožef Stefan Institute, Ljubljana, Slovenia who has expertise in neurobiology and is building resources to study the signaling pathways upstream of the RBPs. The three groups have successfully collaborated in the past and have already produced significant joint research results and publications, which warrant success of the proposed project.
Significance for science
High-throughput sequencing (HTS) allows genome-wide and nucleotide-resolution measurements of the transcriptome and regulation of transcription. A method to study protein-RNA interactions with HTS at high resolution, iCLIP, has been pioneered by our collaborative work. In recent years, iCLIP and related methods have become a central tool for the study of protein-RNA interactions, and are used in hundreds of laboratories around the world. We continue to devise new HTS-based methods, including the proposed pA-seq for the quantification of 3’ end processing. At the same time, HTS-based methods rely heavily on specialized computational tools, which are in great demand and require great effort to design and implement. We have developed such computational tools and provided them as freely available to the research community (https://github.com/tomazc/iCount, https://github.com/mstrazar/iONMF, http://biolab.si/iCLIPro). These tools provide new, very powerful genomic tools for the elucidation of protein-RNA interactions and the advancement of molecular biology.
Significance for the country
The TDP-43 and FUS proteins play an important role in )90% of patients with FTLD or ALS. As such, they are placed at the centre of research into the pathogenesis of these diseases. FTLD accounts for ~10% of all dementia, and ALS is a debilitating motor neuron disease – both diseases have an enormous physical, psychological and economic impact on the community. We have mapped the RNA regulatory networks that are perturbed upon mutations or loss of function of the two proteins. Our results and newly developed computational tools are freely available online to the general research community. A large number of diseases involves defective RNA-binding proteins, but are poorly understood, therefore our tools could enable great progress to understanding fundamental mechanisms of human diseases. The user-friendly database allows experimental scientists to quickly interact with complex data and test new hypotheses. This can be crucial as we move forward to identify the most informative models, which could provide new opportunities for the future studies aimed at the development of new therapeutic strategies. This project importantly improves the efficiency of research in the field of expression regulation. Analysis of HTS (high-throughput sequencing) data is an extremely active field of research in all leading molecular biology laboratories and research universities around the world. With this project, Slovenian researchers have contributed to the development of experimental methods and software tools for HTS, which is increasing the worldwide recognition of Slovenian research excellence and its innovative applications in the field of RNA research. Young scientists and PhD students from UL FRI, UK, and IJS have contribute to the project, which broadened their knowledge and provided opportunities to be involved in cutting-edge, world-class, and high-impact research. PhD students from UL FRI and IJS have been in contact with the Ule group in UK, which has provided invaluable opportunities for students to exchange expertise and design new long-term collaborations. We have promoted the results of our research at international conferences and workshops and have published in leading research journals, which should increase the recognition of Slovenian science. The international research community expressed great interest in our computational tools, which raises an opportunity to develop them further commercially.
Most important scientific results Annual report 2013, 2014, 2015, final report
Most important socioeconomically and culturally relevant results Annual report 2013, 2014, 2015, final report
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