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

人类基因组在空间上是在多个层次上组织的。在几十到几百个DNA的酶的范围内，两个遥远的染色体位点被带到一起形成染色质环。染色质环在整个基因组中发现，它们代表基因组组织的基本单位。它们对基因表达的调节也很重要。染色质环的全基因组组织最近被详细研究，但它仍然是知之甚少的个别染色质环如何改变其形状随着时间的推移。在这个项目中，我们将可视化选定的染色体位点，使用先进的显微镜技术。使用这些，我们可以分析人类细胞中单个染色质环的形成和溶解，此外，还可以通过耗尽候选调节剂和研究细胞中的结果来研究调节染色质环动态的分子机制。此外，为了解释染色质环的动力学，我们将开发数学模型，它将整合染色质环的形成和dissolution.Our最近的数据表明，共同的调节剂促进染色质环的形成和相同染色体位点的重复染色体之间的凝聚力。然而，这两个功能是如何相互联系的，目前尚不清楚。我们将讨论这两种功能是否相互竞争，或者它们是否共同调节，即一起上调或下调。染色体环的调节因子在先天性疾病和某些类型的癌症如膀胱癌和白血病中经常发生突变。为了解决这些疾病是如何发展的，我们将研究这些突变如何改变染色体环的动态行为。总的来说，我们的研究将提供关于基因组组织的基本单位如何在人类细胞中动态调节以及这一过程如何在人类疾病中出错的关键信息。

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.