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Andrea Brand Projects

Supervisor:  Andrea Brand

 

Project 1:  Time to wake up: regulation of stem cell quiescence and proliferation

We use Drosophila and mouse models to study how the local and systemic environments influence neural stem cell behaviour. Stem cells spend much of their time in a mitotically dormant, quiescent, state. However, neural stem cells can generate new neurons in the brain in response to a range of stimuli, including exercise, nutrition and injury. Uncovering the molecular mechanisms that control neural stem quiescence and reactivation is crucial for understanding tissue regeneration under normal and pathological conditions and in response to ageing.

It has been widely accepted that quiescent stem cells are arrested in G0, however, we discovered that quiescent neural stem cells in Drosophila are arrested in either G0 or G2. Furthermore, we showed that G2/G0 heterogeneity directs stem cell function: G2 arrested cells reactivate much more rapidly than G0 cells (Otsuki, L. and Brand, A.H. (2018). Cell cycle heterogeneity directs the timing of neural stem cell activation from quiescence. Science 360, 99-102). The student will use single cell RNA sequencing to identify the transcriptional differences between G2 and G0 stem cells. They will manipulate expression of candidate genes by targeted RNAi or CRISPR to assess their role in regulating quiescence.

Relevant references:

1.  Otsuki, L. and Brand, A.H. (2019). Dorsal-ventral differences in neural stem cell quiescence are induced by p57KIP2/Dacapo. Developmental Cell, 49, 293-300.

2.  Otsuki, L. and Brand, A.H. (2018). Cell cycle heterogeneity directs the timing of neural stem cell activation from quiescence. Science 360, 99-102.

3.  Hakes, A.E., Otsuki, L. and Brand, A.H. (2018). A newly discovered neural stem cell population is generated by the optic lobe neuroepithelium during embryogenesis in Drosophila melanogaster. Development 145(18). doi: 10.1242/dev.166207.

 

Project 2:  Modelling Brain Tumours in Drosophila

It is critical to learn not only how stem cells can be induced to proliferate but also how they return to a quiescent state, as uncontrolled stem cell division can lead to cancer. Our lab uses cutting edge genetic and molecular approaches and advanced imaging techniques to study stem cells and their progeny in vivo. We developed Targeted DamID (or TaDa) to profile genome-wide binding of transcription factors and chromatin factors in specific cell- and tissue-types, including neural lineages. By combining TaDa and single cell sequencing we can profile transcription and epigenetic states throughout development and in response to changing physiological conditions.

We have developed a model of glioblastoma in Drosophila and have mapped the tumour cell of origin. The student will assess the response of these brain tumours to drug treatment, testing both known and previously untested anti-cancer compounds, by monitoring transcriptional and epigenetic changes in the tumours using Targeted DamID and single cell RNA sequencing. 

Relevant references:

1.  Hakes, A.E. and Brand, A.H. (2019). Neural Stem Cell Dynamics: The Development of Brain Tumours. Current Opinion in Cell Biology, 60, 131–138.

2.  van den Ameele, J. and Brand, A.H. (2019). Neural stem cell temporal patterning and brain tumour growth rely on oxidative phosphorylation. eLife. 2019 Sep 12;8. pii: e47887. doi: 10.7554/eLife.47887.

3.  Cheetham, S.W., Gruhn, W.H., van den Ameele, J., Krautz, R., Southall, T.D., Kobayashi, T., Surani, M.A. and Brand, A.H. (2018). Targeted DamID reveals differential binding of mammalian pluripotency factors. Development 145(20). doi: 10.1242/dev.170209.