Three-dimensional interrogation of gene regulation using next generation chromatin conformation capture and super-resolution imaging.

使用下一代染色质构象捕获和超分辨率成像对基因调控进行三维询问。

• 批准号: MR/N00969X/1
• 负责人: Jim Hughes
• 金额: $ 48.71万
• 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: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FN00969X%2F1
• 关键词: Three; dimensional; interrogation; gene; regulation

To form the cells and tissues that make up our bodies requires exquisite control of the activity of our genes. The protein products of genes form the functional and structural components of our cells. Gene expression is controlled by a subgroup of proteins called transcription factors which bind specific sequences in our DNA (also called the "genome"). If this control is altered by sequence changes in the genome then the correct function of our cells is affected and can lead to disease: the particular disease or diseases depend on the types of cells affected. Scientists have become very good at finding the ~ 2% of our DNA that encodes for protein, however it has become clear that other parts of our genome (called regulatory elements) play a critical role in controlling our genes.Regulatory elements are scattered throughout the genome and novel methods that identify such elements show that it is very difficult to understand which gene they control as they do not necessarily control nearby genes, but may affect quite distant genes. A technique called chromosome conformation capture can link regulatory elements to the genes they control by mapping their physical interactions, which are necessary for their activity, but this still does not explain why certain elements can contact and regulate some specific genes but not others. This is an important question because changes in the genome sequence can prevent regulatory elements talking to the correct genes or cause them to talk to the wrong genes with very damaging consequences. The mechanism that makes these interactions specific is unknown, but is thought to be due to the three dimensional arrangement of the genome in the nucleus. The work in this proposal adapts technologies developed by a collaboration between molecular biologists, chemists and computational scientists to visualize these interactions in 3D to understand how certain regulatory elements work with specific genes and how changes in the genome can alter this and cause disease.

为了形成构成我们身体的细胞和组织，需要对我们基因的活动进行精确的控制。基因的蛋白质产物形成了我们细胞的功能和结构成分。基因表达由一组称为转录因子的蛋白质控制，它们结合我们DNA中的特定序列（也称为“基因组”）。如果这种控制被基因组中的序列改变所改变，那么我们细胞的正确功能就会受到影响，并可能导致疾病：特定的疾病取决于受影响的细胞类型。科学家们已经非常善于发现我们DNA中编码蛋白质的2%，但是我们基因组的其他部分（称为监管要素）在控制我们的基因中起着关键作用。调控元件分散在整个基因组中，识别这些元件的新方法表明，很难理解它们控制的是哪个基因，因为它们不一定控制附近的基因。基因，但可能会影响相当遥远的基因。一种称为染色体构象捕获的技术可以通过绘制它们的物理相互作用将调控元件与它们控制的基因联系起来，这是它们活动所必需的，但这仍然不能解释为什么某些元件可以接触和调控某些特定的基因，而不是其他基因。这是一个重要的问题，因为基因组序列的变化可以阻止调控元件与正确的基因交谈，或者导致它们与错误的基因交谈，从而产生非常有害的后果。使这些相互作用特异性的机制尚不清楚，但被认为是由于基因组在细胞核中的三维排列。该提案中的工作采用了分子生物学家，化学家和计算科学家合作开发的技术，以3D方式可视化这些相互作用，以了解某些调控元件如何与特定基因一起工作，以及基因组中的变化如何改变这一点并导致疾病。

项目成果

Predicting the three-dimensional folding of cis-regulatory regions in mammalian genomes using bioinformatic data and polymer models.

• DOI: 10.1186/s13059-016-0909-0
• 发表时间: 2016-03-31
• 期刊: Genome biology
• 影响因子: 12.3
• 作者: Brackley CA;Brown JM;Waithe D;Babbs C;Davies J;Hughes JR;Buckle VJ;Marenduzzo D
• 通讯作者: Marenduzzo D

Fra-1 regulates its target genes via binding to remote enhancers without exerting major control on chromatin architecture in triple negative breast cancers.

• DOI: 10.1093/nar/gkab053
• 发表时间: 2021-03-18
• 期刊: Nucleic acids research
• 影响因子: 14.9
• 作者: Bejjani F;Tolza C;Boulanger M;Downes D;Romero R;Maqbool MA;Zine El Aabidine A;Andrau JC;Lebre S;Brehelin L;Parrinello H;Rohmer M;Kaoma T;Vallar L;Hughes JR;Zibara K;Lecellier CH;Piechaczyk M;Jariel-Encontre I
• 通讯作者: Jariel-Encontre I

A tissue-specific self-interacting chromatin domain forms independently of enhancer-promoter interactions.

• DOI: 10.1038/s41467-018-06248-4
• 发表时间: 2018-09-21
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Brown JM;Roberts NA;Graham B;Waithe D;Lagerholm C;Telenius JM;De Ornellas S;Oudelaar AM;Scott C;Szczerbal I;Babbs C;Kassouf MT;Hughes JR;Higgs DR;Buckle VJ
• 通讯作者: Buckle VJ

A tissue-specific self-interacting chromatin domain forms independently of enhancer-promoter interactions

组织特异性自相互作用染色质结构域的形成独立于增强子-启动子相互作用

• DOI: 10.1101/234427
• 发表时间: 2017
• 作者: Brown J

Author Correction: Capture-C: a modular and flexible approach for high-resolution chromosome conformation capture.

作者更正：Capture-C：一种用于高分辨率染色体构象捕获的模块化且灵活的方法。

• DOI: 10.1038/s41596-023-00860-5
• 发表时间: 2023
• 期刊: Nature protocols
• 影响因子: 14.8
• 作者: Downes DJ