The human genome is spatially organised at multiple levels within the nucleus during interphase. Chromatin loops are basic units of genome organisation [1] – they span tens to hundreds kilobases of DNA and often facilitate enhancer–promoter interaction for gene expression. The formation of a chromatin loop relies on cohesins and the CCCTC-binding factor (CTCF). The 4C and Hi-C analyses revealed formation of chromatin loops genome-wide. However, it is still unclear how the conformations of chromatin loops change over time and what molecular mechanisms regulate such changes.
Meanwhile, it has been found that mutations in cohesins and their regulators cause congenital disorders and specific types of cancers. It is suspected that these mutations impair chromosome organisation, leading to such diseases. However, the mechanisms by which defects of cohesins and their regulators lead to these diseases are unknown.
The Tanaka group have been studying dynamics of mitotic chromosomes by visualising a chosen chromosome region in live-cell imaging [2]. They have also been studying dynamic regulation of cohesins involved in sister chromatid cohesion [3]. Using such expertise, the Tanaka group start investigating dynamics of chromatin loops in interphase. For this, they visualize conformation of chromatin loops and analyse their dynamic changes over time in human cells.
In this PhD project, a student will investigate dynamics of chromatin loops further by real-time imaging of human cells. For example, he/she will address how dynamics of chromatin loops change in the cell cycle and how cohesins and their regulators are involved in dynamic formation and dissolution of chromatin loops. These analyses will establish an important framework for the real-time dynamics of chromatin loops.
Furthermore, to obtain insight into how mutations of cohesins and their regulators change chromosome organisation and lead to congenital disorders and cancers, the student will study how these mutations affect the dynamics of chromatin loops. He/she will focus on a) NIPBL haplo-insufficiency, which causes Cornelia de Lange Syndrome, and b) STAG2 mutations, which are frequently found in cancers such as bladder cancer, Ewing sarcoma and myeloid leukaemia.
The student, who will take this project, will learn the latest methods in molecular cell biology such as CRISPR/Cas9 genome editing, siRNA and Live FISH as well as state-of-the-art microscopy including super resolution live-cell imaging and advanced AI-based image analyses.
For further information on the CSC programme please visit https://www.lifesci.dundee.ac.uk/phdprog/phd-studentships/programmes/china-scholarship-council-csc-programme
To apply for this project please visit https://www.lifesci.dundee.ac.uk/apply-now
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