Regulation of mammalian genome architecture and mobility in pluripotent and transformed cells

在这个项目中，我们计划研究哺乳动物基因组的结构和流动性。目前尚不清楚细胞周期、细胞分化过程中染色质结构的维持或重组如何影响染色质运动。此外，有大量证据表明，肿瘤细胞中的染色质组织和动力学发生了变化。我们开发了成像和图像分析方法来分析不同分辨率水平的基因组结构，并与不同层次的基因组组织(DNA环和拓扑相关区域)相对应。与此同时，我们已经建立并表征了细胞系统，并将研究染色质组织和移动性是否以及如何与随机基因转录有关，这是多能细胞和癌基因转化细胞的主要特征。因此，我们将一方面关注细胞的多能性及其丧失，另一方面关注癌基因诱导的细胞转化。我们将开发新的基于深度学习的图像分析计算方法，基于不同细胞类型、不同分辨率水平的显微图像，精确定量染色质的高阶结构及其迁移率。这项工作应该提供关于哺乳动物基因组的组织和移动性以及这如何调节或被基因组过程调节的洞察力。

In this project, we plan to investigate the architecture and mobility of the mammalian genome. It is unclear how the chromatin structure maintenance or reorganization during the cell cycle, cellular differentiation affects or is affected by chromatin motion. Moreover, there is substantial evidence that chromatin organization and dynamics is altered in tumor cells. We have developed imaging and image analysis methods to analyze genome structures at different resolution levels and corresponding to different hierarchical levels of organization of the genome (DNA loops and topologically associated domains). In parallel, we have generated and characterized cellular systems and will study whether and how chromatin organization and mobility relate with stochastic gene transcription, which are main characteristics of pluripotent as well as oncogene-transformed cells. Hence, we will focus, on the one hand, on cellular pluripotency and loss thereof and, on the other hand, on oncogene-induced cellular transformation. We will develop novel computational methods for image analysis based on deep learning to accurately quantify the chromatin higher-order structures and their mobility based on microscopy images of different cell types at different resolution levels. This work should provide insights on the organization and mobility of the mammalian genome and how this regulates or is regulated by genomic processes.