System Biological Determination of the Epigenomic Structure-Function Relation: EpiGenSys

我们的遗传信息存储在由DNA编码的碱基序列中，而贯穿每条人类染色体长度的DNA分子可以说是已知的最长和最重要的生物分子。但是，尽管我们现在知道了它们的DNA序列，但我们仍然几乎不知道这些DNA是如何在活细胞核内的3D空间中折叠的。常识表明，在这种表面上的纠葛中，一定有某种潜在的秩序。因此，3-D动态结构与功能的关系--遗传信息的存储和表达--仍然是我们这个时代尚未解决的中心问题之一。很明显，基因组是巨大的共同进化和相互交织的分子存储机器，能够操纵和制造信息：遗传信息被编码在这些长分子中并沿着这些长分子编码，这些分子通过多维相互作用和调控网络不断地在空间和时间上进行修改。因此，充分理解结构-功能关系不仅需要了解线性碱基对的组成，还需要了解其结构和动态组织。人类基因组在几个层面上编码信息：i)著名的DNA双螺旋，ii)缠绕在蛋白质复合体(核小体)周围的信息，iii)并凝聚成更高阶染色质纤维，iv)折叠成环，v)这些亚域又聚集成染色体亚域，vi)形成‘领地’，vii)在细胞核内以复杂的方式排列。在所有这些层面上，都可以找到充当代码和影响功能的修改。因此，在‘EpiGenSys’中，我们建立了一个独特的欧洲科学家联盟，目的是在确定和理解DNA序列、3-D折叠和系统能够获取和读取(‘转录’)信息的方式之间的关系方面取得重大突破。使用真正的跨学科方法，我们计划整合以下一组项目：i)在核小体水平上对局部动态结构的研究，在纤维水平上对全球动态结构的研究。二)确定染色体内/染色体间的相互作用和区域的组织。三)分析基因读数--转录状态--及其与基本结构的关系。IV)(使用超级计算机)在核小体、纤维和整个染色体水平上的结构模拟，以提供理论上的见解。V)将i)至iv)集成到整个系统的数学模型中，该模型将使用便于查看(和操纵)所有不同类型的数据的特殊网络浏览器来访问。我们期望通过实验和理论之间的反复循环，我们将能够解决基因组时代的一个中心问题--结构影响基因活性的方式(反之亦然)。项目一)至项目三)涉及(湿)实验科学(细胞和分子生物学)，而项目四)和项目五)利用计算机和数学模型(因此涉及数学家、物理学家和生物信息学家)。公关库克将参与项目II)、III)和IV)，因此将在文化鸿沟的两边发挥作用。

Our genetic information is stored in the base sequence encoded by our DNA, and the DNA molecules that run the length of each human chromosome are arguably the longest and most important biomolecules known. But although we now know their DNA sequences, we still know almost nothing about how that DNA is folded in 3-D space within the nucleus of a living cell. Common sense suggests there must be some underlying order within the apparent tangle. As a result, the relation of the 3-D dynamic architecture with function - the storage and expression of genetic information - remains one of the central unresolved issues of our time. It has become clear that genomes are tremendous coevolutionary and interwoven molecular storage machines able to manipulate and fabricate information: the genetic information is coded in and along these long molecules, and these molecules are continually being modified spatially and temporally through a multi-dimensional interaction and regulatory network. Therefore, a full understanding of structure-function relationships requires knowledge not only of the linear base-pair composition, but also of its structural and dynamic organization. The human genome encodes information on several levels: i) the famous DNA double helix, ii) which winds around a protein complex (the nucleosome), iii) and condenses into a higher-order 'chromatin' fiber, iv) that is folded into loops, v) which aggregate in turn into chromosomal subdomains, vi) that form 'territories', vii) which are arranged in a complex way in the nucleus. Modifications acting as a code and affecting function are found at all these levels. Therefore, in 'EpiGenSys' we have established an unique consortium of European scientists with the aim of achieving a major breakthrough in the determination and understanding of the relation between DNA sequence, the 3-D folding, and the way the system is able to access and read ('transcribe') the information. Using a truly inter-disciplinary approach, we plan to integrate the following set of projects: i) The investigation of the dynamic structure locally at the level of the nucleosome and globally at the level of the fiber. ii) The determination of intra/inter chromosomal interactions and the organization of territories. iii) The analysis of the genetic readouts - the transcriptional states - and their relation to the underlying structure. iv) The simulation (using super-computers) of the structure at the level of nucleosomes, fibers, and whole chromosomes to provide theoretical insight. v) The integration of i) to iv) into a mathematical model of the whole system that will be accessed using a special web browser that will facilitate the viewing (and manipulation) of all the different kinds of data. We expect through reiterative cycling between experiment and theory that we will be able to address a central issue of the genomic era - the way structure influences gene activity (and vice versa). Projects i) through iii) involve (wet) experimental science (cell and molecular biology), while projects iv) and v) utilize computers and mathematical modelling (and so involve mathematicians, physicists, and bioinformaticians) . PR Cook will be involved in projects ii), iii) and iv), and so will work on both sides of the cultural divide.