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MRC DTP: Dynamics of chromosome organisation: physiology and pathology

School of Life Sciences

About the Project

It is a fundamental biomedical question how human chromosomes are spatially organised within the nucleus. Chromatin loops represent basic units of chromosome organisation and play crucial roles in regulation of gene expression during interphase. When cells proceed from interphase to mitosis, chromosomes undergo drastic structural changes (mitotic chromosome re-organisation), i.e. sister chromatids are resolved from each other and compacted to prepare for chromosome segregation, which occurs later in mitosis.

Regulation of these processes has important medical relevance. Indeed, while disordered chromatin loops cause aberrant gene expression, abnormal mitotic chromosome re-organisation leads to errors in chromosome segregation. Such abnormal chromosome organisation eventually results in human diseases including congenital disorders and cancers. To address physiology and pathology of chromosome organisation, we need to understand how individual chromatin loops change their shapes over time, how sister chromatid resolution and compaction are coordinated in mitosis, and what happens if these processes go wrong.

The proposed PhD project will address these vital questions, using advanced live-cell imaging and mathematical modelling. The Tanaka group has expertise in molecular genetics and live-cell imaging of human cells. We will visualise multiple chromosome loci in different colours, using CRISPR/Cas9 genome editing, dCas9 locus imaging and super-resolution live-cell imaging. We will analyse dynamics of these chromosome loci in context of chromosome organization to understand dynamics of chromatin loop formation/dissolution and sister chromatid resolution/compaction. G. Barton is the academic lead of the Data Analysis Group (DAG), who will develop computer simulation and mathematical modelling of chromosome dynamics, based on the quantitative live-cell imaging data. We will not only investigate how chromosome dynamics are regulated in normal conditions, but will also reveal how they go wrong in disease conditions – e,g. with mutations causing congenital disorders and cancers.

The PhD student, who takes this project, will learn methods in molecular genetics, genome editing, advanced live-cell imaging and image analyses, and will collaborate with bioinformaticians in DAG to develop mathematical modelling and computer simulation. This PhD project will provide a unique opportunity of working on cutting edge biomedical sciences integrating wet-lab and in-silico interdisciplinary approaches.

Funding Notes

Eykelenboom, J.K. et al. Live imaging of marked chromosome regions reveals their dynamic resolution and compaction in mitosis. J. Cell Biol. 218, 1531-52 (2019).

Vasileva V et al. Molecular mechanisms facilitating the initial kinetochore encounter with spindle microtubules. J. Cell Biol, 216, 1609-22 (2017).

Gandhi SR et al. Kinetochore-dependent microtubule rescue ensures their efficient and sustained interactions in early mitosis. Dev Cell, 21, 920-33. (2011).

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