Coordination Funds

真核基因组编码的信息，定义了一般和具体的特点，每种细胞类型。然而，单独的线性DNA序列往往无法预测细胞功能和表型结果。事实上，基因组信息是由许多额外的基因表达控制层修改和调节的。其中之一，染色体的空间折叠，最近已被确定为一个关键的这样的层。空间染色体折叠是通过转录因子的结合以及通过表观遗传机制和生物物理力建立的，这些机制和生物物理力以协调一致的方式作用以调节基因在空间和时间上的表达。因此，研究三维染色质折叠的原理使我们能够揭示其在发育和疾病过程中对基因调控的贡献。该优先计划的主要目标是在与基因组完整性，发育和疾病相关的研究系统中，以高时空分辨率剖析高等后生动物基因组的结构与功能关系。除了汇集从事这一研究领域的德国学术团体的临界质量的明显目标外，我们还希望在这个SPP中举办项目，对模型生物和人类样本进行体外和体内功能和机制研究，以加深我们对基因组结构如何成为细胞和组织生理学基础的理解。所有项目（合作或独立）都应明确和实质性地关注驱动或维持3D染色质折叠的机制和力量及其在基因调控中的作用。设想将先进的分子方法、超分辨率和/或活细胞成像、精确的基因编辑和新型计算工具相结合。因此，包括在第二个SPP资助期内的项目应该：（i）开发和应用可以捕获空间染色质构象的新技术，还可以结合其他基因组特征（例如，转录、组蛋白修饰、DNA甲基化），以解析和追踪细胞核中基因组结构的特征，直至单细胞水平;（ii）在发育或细胞分化期间，在体外和体内剖析3D染色质折叠对基因表达或基因组完整性的功能影响;（iii）通过精确的基因组编辑和患者数据和/或疾病模型将3D染色质折叠与疾病病因学因果联系起来;（iv）开发和应用新的计算方法，使我们能够整合，定量建模和可视化空间基因组组织的最终效应和动态。最后，我们期望该联盟将产生新的知识，使我们更接近于定义一套简约的规则，解释真核染色体的结构与功能的关系。

Eukaryotic genomes encode the information that defines both general and specific characteristics of each cell type. However, the linear DNA sequence alone often fails to predict cellular functions and phenotypic outcomes. In fact, genomic information is modified and regulated by a number of additional layers of gene expression control. One of these, the spatial folding of chromosomes, has been recently identified as a critical such layer. Spatial chromosomal folding is established through binding of transcription factors as well as via epigenetic mechanisms and biophysical forces that act in a concerted manner to regulate gene expression in space and time. Therefore, studying the principles of three-dimensional chromatin folding allow us to unravel its contribution in gene regulation during development and disease. The primary goal of this Priority Program is to dissect the structure-to-function relationship of the genomes of higher metazoans at high spatiotemporal resolution in study systems relevant to genome integrity, development, and disease. Aside from the apparent goal of bringing together a critical mass of German-academia groups engaged in this line of research, we also aspire to host projects in this SPP that undertake in vitro and in vivo functional and mechanistic studies on model organisms and human samples that can deepen our understanding of how genome architecture underlies cell and tissue physiology. All projects (collaborative or standalone) should have a clear and substantial focus on mechanisms and forces driving or maintaining 3D chromatin folding and its role in gene regulation. A combination of advanced molecular methods, super‐resolution and/ or live‐cell imaging, precision genetic editing, and novel computational tools is envisaged. Thus, projects included in this 2nd SPP funding period should: (i) develop and apply novel technologies that can capture spatial chromatin conformation, also in conjunction with other genomic features (e.g., transcription, histone modifications, DNA methylation), to resolve and track features of genomic architecture in the nucleus down to the single cell-level; (ii) dissect the functional impact of 3D chromatin folding on gene expression or genome integrity in vitro and in vivo during development or cell differentiation; (iii) causally connect 3D chromatin folding with disease etiology via precision genome editing and patient data and/or disease models; (iv) develop and apply novel computational approaches allowing us to integrate, quantitatively model, and visualize the end-effects and dynamics of spatial genome organization. In the end, we aspire that the consortium will generate new knowledge bringing us closer to defining a parsimonious set of rules that explain the structure-to-function relationship of eukaryotic chromosomes.