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Study of the role of m6A RNA methylation in the nervous system of Drosophila melanogaster: an in-vivo model to dissect the impact of epitranscriptome reprogramming in physiology and cancer

Periodic Reporting for period 1 - EpiMethFly (Study of the role of m6A RNA methylation in the nervous system of Drosophila melanogaster: an in-vivo model to dissect the impact of epitranscriptome reprogramming in physiology and cancer)

Reporting period: 2017-09-19 to 2019-09-18

The project is focused on understanding the role of RNA modifications and, in particular, one form of RNA methylation (m6A) during normal and aberrant development of the nervous system using a powerful genetic model, such as the fruit fly Drosophila melanogaster. The study of m6A is important for the society because, due to its central biological role, m6A might represent an important target to be exploited for the treatment of brain cancer and other pathologies of the nervous system. However, to do so we need to get a clear understanding of what are m6A targets and the processes that it regulates that is currently missing. The project wanted to address this problem: to give a better and more detailed insight into how m6A affects the biology of the nervous system and the molecular mechanisms underlying this function. More precisely, the project had two main objectives: the first one was to clarify the consequences of perturbing RNA methylation during Central nervous system development in terms of brain connectivity and assembly. The second overall objective was to study if perturbation of m6A plays a role in brain cancer (glioblastoma multiforme GBM) development to get a better insight into how m6A could be exploited for brain cancer therapy.
The work performed in the project was focused on using the fruit fly Drosophila melanogaster as a model to study the biological consequences of perturbing the m6A machinery in vivo both during normal nervous system development and in GBM.
I genetically perturbed the m6A machinery in a time and tissue specific manner and demonstrated that m6A is required for the correct assembly of the brain circuitry, that is fundamental for the overall organism development and health. In particular, the presence of m6A on the mRNAs affects the way these molecules are recognized by RNA-binding proteins, with important consequences on their biology. The described results can be exploited in several ways: firstly, the identification of a role of m6A in axon growth and guidance will set the path for further identification of m6A targets involved in this process. Secondly, m6A might represent an interesting therapeutic target for neurodevelopmental disease.
Moreover, the work performed using a GBM model, highlighted that m6A might play several roles during brain tumor development. In fact, affecting the overall levels of m6A, or the way m6A is recognized by specific “reader” proteins, affects the growth of the tumor. A clear knowledge of the role of m6A in tumor development is still lacking, as well as an understanding of what are the m6A target relevant for this pathology. Therefore, the results of this work can be exploited to understand the molecular mechanisms underlying tumor formation and growth. Moreover, m6A might represent a good therapeutical target to treat these aggressive tumors.
To disseminate the results of this work I participated to two international (European Drosophila Research Conference (EDRC) 2017 and 2019) and one national (XIX Congresso Nazionale AIBG) meetings. Moreover, I prepared a scientific publication that is currently under revision in a peer reviewed scientific journal and that has been already deposited on BioRxiv, the preprint server for biology (Soldano A. and Worpenberg L et al. doi: . This publication describes the results of the analysis of m6A role in brain development and includes references to the EU funding.
The work performed led to great progress beyond the state of art. In fact, it led to the discovery of a crucial role of m6A in modulating axon growth and guidance during brain development. RNA modifications have emerged in the last decade as critical players that allow to regulate fast and efficiently many aspects of organismal biology and among them, the m6A RNA methylation is the most commonly found on messenger RNAs (mRNA). Many reports have suggested that m6A is involved in nervous system development, neurodegeneration and tumor formation but the mechanisms underlying these functions are still elusive. The results of this project clarified how m6A affects the way RNA-binding protein are able to bind their target RNAs to regulate their levels of translation. It also clarified how this process is required for Central Nervous System circuits to assembly correctly. Therefore, these results bring an important contribution to the state of the art.
Moreover, the work performed using the GBM model, although more preliminary, strongly indicated that opposite perturbation of m6A affects tumor growth. In particular, m6A impacts on the level of proliferation and glia expansion in GBM, as well as on the survival of the animals harbouring the tumor. These results have an important social impact because they imply that targeting the main component of the m6A machinery might not be an efficient strategy to treat cancer due to the broad range of effects that this modulation will achieve.
Summary of the project