Dynamic regulation of chromatin loops by cohesins and CTCF in real time: physiology and pathology

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The human genome is spatially organised at multiple levels. In the range of tens to hundreds kilobases of DNA, two distant chromosome sites are brought together to form a chromatin loop. Chromatin loops are found throughout the genome and they represent basic units of genome organisation. They are also important for regulation of gene expression. The genome-wide organisation of chromatin loops has recently been studied in detail, but it is still poorly understood how individual chromatin loops change their shape over time.In this project, we will visualise selected chromosome sites, using advanced microscopy techniques. Using these we can analyse the formation and dissolution of individual chromatin loops in human cells and, in addition, can study the molecular mechanisms regulating the dynamics of chromatin loops by depleting candidate regulators and studying the outcomes in cells. Moreover, to explain the dynamics of chromatin loops, we will develop mathematical models, which will integrate several steps involved in chromatin-loop formation and dissolution.Our recent data suggest that common regulators facilitate both formation of chromatin loops and cohesion between duplicated chromosomes at the same chromosome sites. However, it is unknown how these two functions are interlinked. We will address whether the two functions compete with each other or whether they are co-regulated, i.e. up-regulated or down-regulated together. Regulators of chromosome loops are often mutated in inborn diseases and some types of cancers e.g. bladder cancer and leukaemia. To address how these diseases develop, we will investigate how such mutations change the dynamic behaviour of chromosome loops. Overall, our study will provide crucial information on how a basic unit of genome organisation is dynamically regulated in human cells and how this process could go wrong in human diseases.