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3D chromatin organisation and regulation in development


MRC London Institute of Medical Sciences (LMS)

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Dr J Vaquerizas No more applications being accepted Funded PhD Project (UK Students Only)
London United Kingdom Biochemistry Bioinformatics Biomedical Engineering Biophysics Cell Biology Data Analysis Evolution Genetics Molecular Biology Statistics

About the Project

The three-dimensional organisation of chromatin in the interphase nucleus plays a crucial role for the correct regulation of gene expression (1). Each cell in your body has a 2 metres-long molecule of DNA that needs to be encapsulated within the physical space of the nucleus, a few microns, while making sure that the regulatory mechanisms that allow your cells to work properly do so. It’s similar to storing furniture inside a storage container when you want to find that box inside a box that has this little thing precious to you – similarly, each cell needs to ensure that they have access to key genetic information at the right time. This organisation is crucial because when it is disrupted, it leads to developmental disorders and cancer (2).

In the last few years we and others have unveiled key principles of how the genome is organised in the 3D space of the nucleus in species ranging from fruit flies to mammals (36). In particular, we have focused on trying to understand key developmental stages during early embryonic development, such as the activation of the zygotic genome and the establishment of cellular fates, where major changes in epigenetic programmes occur (7, 8). However, despite these advances, we still lack a fundamental understanding of how these molecular mechanisms work and their effect in regulating gene expression.

The goal of the current project is to decipher molecular mechanisms by which the three-dimensional organisation of the genome is orchestrated, and their contribution to the establishment of cellular fate. To achieve this goal, in this project you will analyse state-of-the-art genomics datasets (e.g., Hi-C, single cell RNA-seq and ATAC-seq, CUT&TAG, etc.) available for different genetic systems, using advanced computational approaches to integrate them. Overall, this project will help understand how the 3D genome works and will give you comprehensive training in modern molecular biology, computational techniques and data analysis. Previous computational experience (e.g., R, Python, Snakemake, bash scripting), and a crisp analytical mind will be a strong advantage.

For instructions on how to apply, please visit https://lms.mrc.ac.uk/study-here/phd-studentships/lms-3-5yr-studentships/


Funding Notes

This is a fully-funded 3.5 year studentship funded by the Medical Research Council.

The studentship covers all tuition fees with Imperial College London and stipend payments amounting to £21,000pa (paid in monthly instalments) directly to the student.

This funding is available to students eligible for Home Fee Rates only.

References

1. R. Stadhouders, G. J. Filion, T. Graf, Transcription factors and 3D genome conformation in cell-fate decisions. Nature. 569, 345–354 (2019).
2. M. Spielmann, D. G. Lupiáñez, S. Mundlos, Structural variation in the 3D genome. Nat. Rev. Genet. 19, 453–467 (2018).
3. C. B. Hug, A. G. Grimaldi, K. Kruse, J. M. Vaquerizas, Chromatin Architecture Emerges during Zygotic Genome Activation Independent of Transcription. Cell. 169, 216-228.e19 (2017).
4. J. D. P. Rhodes, A. Feldmann, B. Hernández-Rodríguez, N. Díaz, J. M. Brown, N. A. Fursova, N. P. Blackledge, P. Prathapan, P. Dobrinic, M. K. Huseyin, A. Szczurek, K. Kruse, K. A. Nasmyth, V. J. Buckle, J. M. Vaquerizas, R. J. Klose, Cohesin Disrupts Polycomb-Dependent Chromosome Interactions in Embryonic Stem Cells. Cell Rep. 30, 820-835.e10 (2020).
5. K. Kruse, N. Diaz, R. Enriquez-Gasca, X. Gaume, M.-E. Torres-Padilla, J. M. Vaquerizas, Transposable elements drive reorganisation of 3D chromatin during early embryogenesis. bioRxiv, 523712 (2019).
6. N. Díaz, K. Kruse, T. Erdmann, A. M. Staiger, G. Ott, G. Lenz, J. M. Vaquerizas, Chromatin conformation analysis of primary patient tissue using a low input Hi-C method. Nat. Commun. 9, 4938 (2018).
7. E. Ing-Simmons, R. Vaid, X. Bing, M. Levine, M. Mannervik, J. M. Vaquerizas, Independence of chromatin conformation and gene regulation during Drosophila dorsoventral patterning. Nat Genet., in press. DOI:10.1038/s41588-021-00799-x
8. C. B. Hug, J. M. Vaquerizas, The Birth of the 3D Genome during Early Embryonic Development. Trends Genet. 34, 903–914 (2018).
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