Deciphering the regulatory genetic code

破译监管遗传密码

• 批准号: BB/V00736X/1
• 负责人: Jussi Taipale
• 金额: $ 196.69万
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FV00736X%2F1
• 关键词: Deciphering; regulatory; genetic; code

Our project aims to understand how the cell can read the information that is written in its genome. The project is very much a collaboration between biological and computational scientists, who will work closely together to understand basic mechanisms of how cells can tell when and where the genes written in their DNA should be active. In other words, we seek to understand 'the second genetic code'. The first genetic code that describes how DNA sequence is converted to protein sequence was decoded more than 50 years ago, and the first draft of human genome, which describes the sequence of the chemical letters A, C, G and T found in all human cells was published in 2001. However, just knowing the order of the letters is not enough to understand how they instruct cells to function and to grow. Advances in DNA-sequencing have also allowed sequencing of entire genomes of individual humans and we have learnt for instance that sequences of unrelated individuals are different by approximately 10 million DNA bases. These specific variants, and the mechanisms by which they act are largely unknown. This is because most of the changes do not affect protein structure. Instead, the variations are presumed to affect the amount of proteins made in particular cells, by affecting DNA binding of proteins called transcription factors. Our research project aims to understand how the transcription factors read the genomic code. This will also help us to understand how mutations or variations in DNA sequences change the activity of genes. The work is basic research utilizing novel high throughput methods and artificial intelligence based computational data analysis tools. The project will first generate vast amounts of data in a laboratory, and then utilize and understand it using tailor-made computer programs.The work will have immediate benefits to the scientific community in terms of deeper understanding, novel methods and computational tools. The work will also lead to increased understanding of the function of cells during growth and development. In a wider context, the proposed project is part of a broader effort to use advanced genomic and computational tools to understand the basis of human and animal biology. Genetic variants that are located between genes are so common that most plants, animals and people have many of them. To understand their function will be of great benefit to the scientific community in terms of deeper understanding of biological principles, for development of novel experimental methods and computational tools, and also eventually for applications such as plant and animal breeding. In addition, understanding the effect of non-coding genetic variants will help to explain human variation, for example in lifespan and health.

我们的项目旨在了解细胞如何读取写入其基因组的信息。该项目在很大程度上是生物学和计算科学家之间的合作，他们将密切合作，以了解细胞如何判断DNA中的基因何时何地应该活跃的基本机制。换句话说，我们试图理解“第二遗传密码”。第一个描述DNA序列如何转化为蛋白质序列的遗传密码在50多年前被破译，第一个人类基因组草图描述了在所有人类细胞中发现的化学字母A，C，G和T的序列，于2001年出版。然而，仅仅知道字母的顺序还不足以理解它们如何指导细胞发挥功能和生长。DNA测序的进步也允许对人类个体的整个基因组进行测序，例如，我们已经了解到，无关个体的序列大约有1000万个DNA碱基不同。这些特定的变体及其作用机制在很大程度上是未知的。这是因为大多数变化不会影响蛋白质结构。相反，这些变异被认为是通过影响被称为转录因子的蛋白质的DNA结合来影响特定细胞中蛋白质的数量。我们的研究项目旨在了解转录因子如何读取基因组密码。这也将帮助我们了解DNA序列的突变或变异如何改变基因的活性。这项工作是利用新的高通量方法和基于人工智能的计算数据分析工具的基础研究。该项目将首先在实验室中生成大量数据，然后使用定制的计算机程序来利用和理解这些数据。这项工作将在更深入的理解、新方法和计算工具方面为科学界带来直接利益。这项工作还将导致对细胞在生长和发育过程中功能的理解。在更广泛的背景下，拟议的项目是使用先进的基因组和计算工具来了解人类和动物生物学基础的更广泛努力的一部分。位于基因之间的遗传变异是如此普遍，以至于大多数植物，动物和人类都有许多。了解它们的功能将有利于科学界更深入地理解生物学原理，开发新的实验方法和计算工具，并最终用于植物和动物育种等应用。此外，了解非编码遗传变异的影响将有助于解释人类的变异，例如在寿命和健康方面。

项目成果

Pioneer factors - key regulators of chromatin and gene expression.

先锋因素 - 染色质和基因表达的关键调节因子。

• DOI: 10.1038/s41576-023-00648-z
• 发表时间: 2023
• 期刊: Nature reviews. Genetics
• 作者: Bulyk ML

Hold out the genome: a roadmap to solving the cis-regulatory code.

坚持基因组：解决顺式监管代码的路线图。

• DOI: 10.17863/cam.105709
• 发表时间: 2024
• 作者: De Boer C

Structural insights into the interaction between transcription factors and the nucleosome

转录因子与核小体之间相互作用的结构见解

• DOI: 10.1016/j.sbi.2021.06.016
• 发表时间: 2021
• 期刊: Current Opinion in Structural Biology
• 影响因子: 6.8
• 作者: Morgunova E

DNA-guided transcription factor cooperativity shapes face and limb mesenchyme.

DNA 引导的转录因子协同作用塑造面部和肢体间质。

• DOI: 10.1101/2023.05.29.541540
• 发表时间: 2023
• 期刊: bioRxiv : the preprint server for biology
• 作者: Kim,Seungsoo;Morgunova,Ekaterina;Naqvi,Sahin;Bader,Maram;Koska,Mervenaz;Popov,Alexander;Luong,Christy;Pogson,Angela;Claes,Peter;Taipale,Jussi;Wysocka,Joanna
• 通讯作者: Wysocka,Joanna

Hold out the genome: a roadmap to solving the cis-regulatory code

• DOI: 10.1038/s41586-023-06661-w
• 发表时间: 2023-12-13
• 期刊: NATURE
• 影响因子: 64.8
• 作者: de Boer，Carl G.;Taipale，Jussi
• 通讯作者: Taipale，Jussi