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mRNA epigenetics: Characterization of novel layer of gene regulation for essential brain functions

Primary Supervisor: Dr Matthias Soller, School of Biosciences

Secondary supervisor: Saverio Brogna

Leicester collaborator: Cyril Dominguez

PhD project title: mRNA epigenetics: Characterization of novel layer of gene regulation for essential brain functions

University of Registration: University of Birmingham

Project outline:

For over 40 years we know about modified nucleotides in mRNA, but the emerging field of epitranscriptomics is still in its infancy in developing methods for accurate global detection of mRNA modifications. Identifying writers, readers and erasers is ongoing, but how writers recognize target RNAs, how different readers distinguish targets and what the role of eraser is remains to be determined. Moreover, functions for these essential modifications are largely elusive.

Recent characterization of the FTO (fat mass and obesity associated) gene as a demethylase of N6-methyladenosine (m6A) indicates key roles for mRNA methylation in neuronal control of body weight[1]. FTO, as well as writers and readers are highly expressed in the brain and have been associated with neurological disorders such as depression, epilepsy and neurodegenerative diseases.

We use a Drosophila genetic model system to investigate the biological function of these modifications and how they change during ageing [2]. Our aim is to identify which mRNAs are modified and where in these mRNAs modifications are localised. Furthermore, we aim to characterize the molecular machinery including structural analysis that places these modifications and the signalling pathways that regulate the dynamics of them. Lastly, we like to know the biological functions for these modifications, in particular how they impact on metabolic homeostasis, feeding and other behavior and age-related neuronal functions including learning and memory [3-7].

References:

  1. Dezi, V., Ivanov, C., Haussmann, I. U. and Soller, M. (2016) mRNA modifications and their role in development and disease. Biochem. Soc. Trans. 44: 1385-93.
  2. Haussmann, I.U., Bodi, Z., Sanchez-Moran, E., Mongan, N., Archer, N., Fray, R., and Soller, M. (2016) m6A potentiates Sxl alternative pre-mRNA splicing for robust Drosophila sex determination. Nature, doi:10.1038/nature20577.
  3. Roignant, J.Y. and Soller, M. (2017) m6A in mRNA: An ancient mechanism to fine tune gene expression. TiG 33: 380-390.
  4. Knuckles, P., Lence, T., Haussmann, I.U., Jacob, D., Kreim, N., Carl, S.H., Masiello, I., Hares, T., Villasenor, R., Hess, D., Andrade-Navarro, M.A., Biggiogera, M., Helm, M., Soller, M., Buhler, M. and Roignant, J.Y. (2018) Zc3h13/Flacc is required for adenosine methylation by bridging the mRNA binding factor Rbm15/Spenito to the m6A machinery component Wtap/Fl(2)d. Genes&Development 32: 415-429.
  5. Balacco, D.L. and Soller, M. (2019) The m6A writer: Rise of a machine for growing tasks. Biochemistry 58: 363-378.
  6. Anreiter, I., Mir, Q., Simpson, J., Janga, S. C. and Soller, M. (2020) New twists on detecting mRNA modification dynamics. Trends in Biotechnology, 39: 72-89.
  7. Bawankar, P., Lence, T., Paolantoni, C., Haussmann, I.U., Kazlauskiene, M., Jacob, D., Heidelberger, J., Richter, F., Nallasivan, M.P., Morin, V., Kreim, N., Beli, P., Helm, M., Jinek, M., Soller*, M. and Roignant*, JY (2021) Hakai is required for stabilizing core components of the m6A mRNA methylation machinery. Nature Communications, 12: 3778. *Co-corresponding author.

BBSRC Strategic Research Priority: Understanding the Rules of Life: Neuroscience and behaviour & Integrated Understanding of Health: Ageing & Diet & Health

    Techniques that will be undertaken during the project:

    This project will incorporate a wide range of molecular and cell biology techniques, which will be applied by using the genetic model organism Drosophila, including, transgenesis and CRISPR/Cas9 mutagensis, and various cell culture models. This project will also analyse the impact of mRNA methylation on behaviour and neuronal function. The project will make use of state-of-the-art cellular imaging to study mRNA methylation in cells. Further, we will employ structural characterization of mRNA methylation components, apply statistical analysis of data and use molecular modelling of structural information to make predictions how mRNA methylation takes place in cells.

    Contact: Dr Matthias Soller, University of Birmingham