Coordination Project for the Priority Programme "Spatial Genome Architecture in Development and Disease

从人类基因组的第一个完整草图开始，很明显，线性遗传信息不足以充分解释其许多基因组功能及其复杂的调节。区分单个细胞和组织的身份和功能的不是它们的基因组内容，而是它们的~20,000个基因各自的调控。基因调控在很大程度上依赖于近端和远端的调控元件，它们通过染色质环来确保与目标启动子的物理接近。由此产生的染色体在核中的空间(3D)组织现在被认为对基因调控和转录输出具有深远的影响。为了开发这一新兴的3D基因组学领域，SPP将有以下主要目标：(1)开发和应用新的和现有的技术来解决染色体构象如何调节的长期存在的问题；(2)从功能上剖析3D染色质折叠在细胞刺激、分化或发育过程中对体外和体内模型的影响；(3)研究3D染色质折叠在疾病病理学中的作用，以了解这种被低估的疾病机制；(4)开发和应用新的计算工具和模型来预测3D基因组折叠动力学如何转化为基因组输出的变化；(5)召集一个跨学科的科学家小组，在德国研究界推进和巩固这一新兴主题。通过关注染色质折叠和基因调控，本SPP解决的生物医学领域远远超出了对基因及其功能的研究，以充分了解它们的调控。在过去十年基因组学最重要的发现之一的基础上，我们进一步研究染色质折叠如何控制分化、发育和疾病，从而解决生命科学中的一个相关问题：如何在基因组水平上实现细胞个性。一旦破译，这些规则将允许我们预测不同的细胞如何对发育或疾病表现的信号线索做出反应。

Already from the first complete draft of the human genome, it became apparent that the linear genetic information would not suffice to fully explain its many genomic functions and their complex regulation. What differentiates the identity and functions of individual cells and tissues is not their genomic content, but the regulation of each of their ~ 20,000 genes. Gene regulation is critically dependent on proximal and distal regulatory elements that act via chromatin looping to ensure physical proximity with their target promoters. The resulting spatial (3D) organization of chromosomes in the nucleus is now understood to have profound effects on gene regulation and transcriptional output. To exploit this emerging field of 3D genomics, The SPP will have the following major aims: (1) develop and apply novel and existing technologies to address the long-standing question of how chromosome conformation is regulated; (2) functionally dissect the impact of 3D chromatin folding on in in vitro and in vivo models during cell stimulation, differentiation or development; (3) investigate the role of 3D chromatin folding in disease pathology to understand this under-appreciated disease mechanism; (4) develop and apply novel computational tools and models to predict how 3D genome folding dynamics translate into changes in genomic output; (5) bring together an interdisciplinary group of scientists to advance and consolidate this emerging topic within the German research community.By focusing on chromatin folding and gene regulation, this SPP addresses a field of biomedicine that goes far beyond the study of genes and their function, to fully understand their regulation. Building on one of the most important discoveries in Genomics in the past decade, we take the next step in investigating how chromatin folding governs differentiation, development and disease, thereby addressing a pertinent question in Life Sciences: how cellular individuality is achieved at a genomic level. Once deciphered, these rules will allow us to predict how different cells respond to signaling cues upon development or disease manifestation.