Deciphering the Mechanisms of Modulation of DNA Accessibility in Chromatin: Discovery of Novel Pioneer Transcription Factors

在真核细胞中，DNA以染色质的形式包装，大约一米的DNA应该适合几微米大小的细胞核。同时，DNA在转录和复制过程中应具有高时空精度的动态访问。这个难题多年来一直困扰着研究人员。有人认为，这种极高程度的DNA压缩可以通过在染色质组织的多个水平上接合不同的结构和调节大分子来实现，其中核小体代表包装的基本构件。一些大分子可以渗透到相对封闭的染色质状态，并特异性地与核小体结合。 在人类中，大约有2000个因子控制着其靶基因的表达。它们中的一些包括被充分研究的常规转录因子，这些转录因子与可接近的DNA结合，而另一些，所谓的先锋转录因子，可以靶向致密的染色质。先锋转录因子可以直接识别它们在核小体上的结合位点，使DNA更容易接近，并协同参与其他转录因子的激活。绝大多数人类先驱转录因子是未知的，其结合位点的位置，结合和调节机制仍有待确定。利用核小体定位，转录因子结合位点和三维结构数据的大规模实验数据，该研究计划将开发各种计算技术，包括分子建模，分子动力学模拟和机器学习，以破译负责先锋转录因子结合和调节的物理化学机制。这项工作将创建尖端的计算开放获取工具，并将在局部基因组规模上推进染色质调控的概念框架。这可以为创新和有前途的表观遗传疗法的设计开辟新的途径。HQP培训将培养出能够在跨学科领域工作的研究人员，并在计算建模和机器学习方面拥有最先进的资格。

In eukaryotic cells DNA is packed in the form of chromatin, about one meter of the DNA should fit into the nucleus of the size of several microns. At the same time, DNA should be dynamically accessed during the transcription and replication processes with high spatiotemporal precision. This dilemma has been puzzling researchers for many years. It has been argued that this extremely high degree of DNA compaction can be achieved by engaging different structural and regulatory macromolecules at multiple levels of chromatin organization, where nucleosomes represent elementary building blocks of packaging. Some macromolecules can infiltrate the relatively closed chromatin states and specifically bind to nucleosomes. There are about two thousand factors which control the expression of their target genes in human. Some of them include well-studied conventional transcription factors that bind to accessible DNA, whereas others, so-called pioneer transcription factors, can target compact chromatin. Pioneer transcription factors may directly recognize their binding sites on nucleosomes, make DNA more accessible and cooperatively engage other factors for transcription activation. The vast majority of human pioneer transcription factors are not known, the locations of their binding sites, mechanisms of binding and regulation remain to be determined. Using large-scale experimental data on nucleosome positioning, transcription factor binding sites and three-dimensional structural data, this research program will develop various computational techniques including molecular modelling, molecular dynamics simulations and machine learning to decipher physicochemical mechanisms responsible for pioneer transcription factor binding and regulation. This work will create cutting-edge computational open-access tools and will advance a conceptual framework of chromatin regulation at the local genomic scale. This can open new avenues for the design of innovative and promising epigenetic therapies. The HQP training will produce researchers which are capable to work in interdisciplinary fields and have state-of-the-art qualifications in computational modelling and machine learning.