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

表观基因组结构-功能关系的系统生物学测定：EpiGenSys

• 批准号: BB/I00467X/1
• 负责人: Peter Cook
• 金额: $ 48.1万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2010
• 资助国家: 英国
• 起止时间: 2010 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FI00467X%2F1
• 关键词: System; Biological; Determination; Epigenomic; Structure

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.

我们的遗传信息存储在由我们的DNA编码的碱基序列中，并且运行每个人类染色体长度的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，我们仍然对DNA在活细胞核内的三维空间中是如何折叠的几乎一无所知。常识表明，在表面上的混乱中一定有某种潜在的秩序。因此，三维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核心问题之一。很明显，基因组是巨大的共同进化和交织的分子存储机器，能够操纵和制造信息：遗传信息编码在这些长分子中，并沿着这些长分子，这些分子通过多维相互作用和调控网络在空间和时间上不断修改。因此，要充分理解结构-功能关系，不仅需要线性碱基对组成的知识，还需要其结构和动态组织的知识。人类基因组在几个层次上编码信息：i）著名的DNA双螺旋，ii）缠绕在蛋白质复合物（核小体）周围，iii）并浓缩成高阶“染色质”纤维，iv）折叠成环，v）依次聚集成染色体子域，vi）形成“领土”，vii）以复杂的方式排列在细胞核中。在所有这些层次上都可以发现作为代码和影响功能的修改。因此，在“EpiGenSys”中，我们建立了一个由欧洲科学家组成的独特联盟，目的是在确定和理解DNA序列、3-D折叠以及系统能够访问和读取（“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）在核小体水平上局部和在纤维水平上全局的动态结构的研究。ii）确定染色体内/间相互作用和区域的组织。iii）分析遗传读数-转录状态-及其与底层结构的关系。iv）在核小体、纤维和整个染色体水平上模拟（使用超级计算机）结构，以提供理论见解。v）将i）至iv）整合到整个系统的数学模型中，该模型将使用特殊的网络浏览器访问，这将有助于查看（和操作）所有不同种类的数据。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核心问题-结构影响基因活性的方式（反之亦然）。项目i）到iii）涉及（湿）实验科学（细胞和分子生物学），而项目iv）和v）利用计算机和数学建模（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工作。

项目成果

Dissecting the nascent human transcriptome by analysing the RNA content of transcription factories.

• DOI: 10.1093/nar/gkv390
• 发表时间: 2015-08-18
• 期刊: Nucleic acids research
• 影响因子: 14.9
• 作者: Caudron-Herger M;Cook PR;Rippe K;Papantonis A
• 通讯作者: Papantonis A

The proteomes of transcription factories containing RNA polymerases I, II or III.

• DOI: 10.1038/nmeth.1705
• 发表时间: 2011-09-25
• 期刊: NATURE METHODS
• 影响因子: 48
• 作者: Melnik, Svitlana;Deng, Binwei;Papantonis, Argyris;Baboo, Sabyasachi;Carr, Ian M.;Cook, Peter R.
• 通讯作者: Cook, Peter R.

Splicing of many human genes involves sites embedded within introns.

许多人类基因的剪接涉及嵌入内含子中的位点。

• DOI: 10.1093/nar/gkv386
• 发表时间: 2015-05-19
• 期刊: Nucleic acids research
• 影响因子: 14.9
• 作者: Kelly S;Georgomanolis T;Zirkel A;Diermeier S;O'Reilly D;Murphy S;Längst G;Cook PR;Papantonis A
• 通讯作者: Papantonis A

Enhancers and silencers: an integrated and simple model for their function.

• DOI: 10.1186/1756-8935-5-1
• 发表时间: 2012-01-09
• 期刊: Epigenetics & chromatin
• 影响因子: 3.9
• 作者: Kolovos P;Knoch TA;Grosveld FG;Cook PR;Papantonis A
• 通讯作者: Papantonis A

Dynamic Reconfiguration of Long Human Genes during One Transcription Cycle

• DOI: 10.1128/mcb.00179-12
• 发表时间: 2012-07-01
• 期刊: MOLECULAR AND CELLULAR BIOLOGY
• 影响因子: 5.3
• 作者: Larkin, Joshua D.;Cook, Peter R.;Papantonis, Argyris
• 通讯作者: Papantonis, Argyris