Understanding the regulation and topological organisation of DNA in the human genome

了解人类基因组中 DNA 的调控和拓扑组织

• 批准号: MR/J00913X/1
• 负责人: Nick Gilbert
• 金额: $ 352.29万
• 依托单位: University of Edinburgh
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2012
• 资助国家: 英国
• 起止时间: 2012 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FJ00913X%2F1
• 关键词: Understanding; regulation; topological; organisation; DNA

In every mammalian cell DNA is packaged into chromatin, a massive nucleoprotein complex. As fundamental nuclear processes such as gene transcription, replication and repair occur in this environment it is important for us to understand chromatin and genome architecture. We have recently developed an assay for mapping high resolution DNA topology (folding) and have discovered that DNA in cells is organised into DNA "topological domains" consisting of over and under wound DNA. In this proposal we plan to investigate these topological domains across the human genome and investigate how they influence gene expression programmes, DNA replication and chromosome stability. In many human diseases including cancer the genome becomes fragile and certain regions of the genome have a propensity to becoming unstable. We will investigate the DNA topology and chromatin organisation of these fragile regions and identify the factors that make them unstable. Our research will enable us to characterise the mechanistic basis for many chromosomal aberrations and identify approaches that can be use to reduce the likelihood of genome instability. One of the first steps in cancer is the acquisition of genome instability. Characterising this process, will better enable us to comprehend the factors and mechanism involved and may in future enable us to either better detect early changes in cancer or develop new approaches for reducing the likelihood of cancer growth.

在每个哺乳动物细胞中，DNA 都被包装成染色质（一种巨大的核蛋白复合物）。由于基因转录、复制和修复等基本核过程发生在这种环境中，因此了解染色质和基因组结构对我们来说非常重要。我们最近开发了一种用于绘制高分辨率 DNA 拓扑（折叠）的分析方法，并发现细胞中的 DNA 被组织成由伤口上方和下方 DNA 组成的 DNA“拓扑域”。在本提案中，我们计划研究人类基因组中的这些拓扑结构域，并研究它们如何影响基因表达程序、DNA 复制和染色体稳定性。在包括癌症在内的许多人类疾病中，基因组变得脆弱，并且基因组的某些区域有变得不稳定的倾向。我们将研究这些脆弱区域的 DNA 拓扑结构和染色质组织，并找出导致它们不稳定的因素。我们的研究将使我们能够描述许多染色体畸变的机制基础，并确定可用于降低基因组不稳定可能性的方法。癌症的第一步是获得基因组不稳定性。表征这一过程将使我们能够更好地理解所涉及的因素和机制，并可能在未来使我们能够更好地检测癌症的早期变化或开发新的方法来降低癌症生长的可能性。

项目成果

Book Review: Functional Analysis of DNA and Chromatin

书评：DNA 和染色质的功能分析

• DOI: 10.3109/10520295.2014.942370
• 发表时间: 2014
• 期刊: Biotechnic & Histochemistry
• 影响因子: 1.6
• 作者: Boteva L

Polymer Simulations of Heteromorphic Chromatin Predict the 3-D Folding of Complex Genomic Loci

异形染色质的聚合物模拟预测复杂基因组位点的 3D 折叠

• DOI: 10.1101/380196
• 发表时间: 2018
• 作者: Buckle A

Centromere transcription allows CENP-A to transit from chromatin association to stable incorporation.

• DOI: 10.1083/jcb.201611087
• 发表时间: 2018-06-04
• 期刊: The Journal of cell biology
• 作者: Bobkov GOM;Gilbert N;Heun P
• 通讯作者: Heun P

Polymer Simulations of Heteromorphic Chromatin Predict the 3D Folding of Complex Genomic Loci.

• DOI: 10.1016/j.molcel.2018.09.016
• 发表时间: 2018-11-15
• 期刊: Molecular cell
• 影响因子: 16
• 作者: Buckle A;Brackley CA;Boyle S;Marenduzzo D;Gilbert N
• 通讯作者: Gilbert N

Functional characteristics of novel pancreatic Pax6 regulatory elements.

• DOI: 10.1093/hmg/ddy255
• 发表时间: 2018-10-01
• 期刊: Human molecular genetics
• 影响因子: 3.5
• 作者: Buckle A;Nozawa RS;Kleinjan DA;Gilbert N
• 通讯作者: Gilbert N