The regulation of transcriptional bursting by superenhancers

超级增强子对转录爆发的调节

基本信息

批准号：
MR/X001210/1
负责人：
Douglas Higgs
金额：
$ 57.22万
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：
2022
资助国家：
英国
起止时间：
2022 至无数据
项目状态：
未结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FX001210%2F1
关键词：
regulation transcriptional bursting superenhancers

项目摘要

The human body is made up of trillions of cells. Each single cell contains the information in its DNA to encode a new individual. The code comes in the form of genes that contain the information to make specific proteins, and regulatory elements (called enhancers) that switch the genes on and off in different tissues, and at different times in development. It is hard to imagine that one could line up 5 or 6 cells across a human hair (60-70 microns). Development of the first microscopes in the 17th century enabled scientists to see such minute structures for the first time. Over the next 300 years, microscopes have been developed so that we can now visualise subdomains that stretch across just one thousandth of the diameter of the cell (60-70 nanometers). So called "super-resolution" microscopes are now enabling us to visualise how enhancers and genes interact to read the genetic code and over the past decade it has been possible to visualise the code being read by creating real-time movies. This new approach to understanding biology at such high resolution, referred to as the nanoscale, is at the limits of what is currently possible in studying biology and so it has been critical to establish very well understood systems that enable us to verify these nanoscale findings by comparing new results with previous analyses of the model locus. In our laboratory we study expression of a gene encoding alpha-globin which contributes to the synthesis of the red cell pigment (haemoglobin). How this gene is switched on and off is probably better understood that almost any other gene. We have shown that the alpha gene is controlled by five enhancers which act as an integrated unit which comes into physical proximity with its target gene as it switches it on. By labelling the RNA produced by gene with a fluorescent probe we have recently shown by live imaging, that when activated, the gene is not continuously active but pulses on and off over time. This is a key mechanism underlying the regulation of gene expression. In the current proposal, we are investigating this mechanism and in particular asking if it is regulated by the enhancer. We will do this by comparing the pattern of gene expression with no enhancers and then how this is modified by re-introducing the five enhancers in various informative combinations. Finally, we will test our findings in their clinical context by examining how natural mutations of the human enhancers are correlated with changes in the red cells of affected individuals. By obtaining a complete understanding of gene regulation, we aim to find out how genes are normally switched on and off, how this is perturbed in human genetic disease and how we might use gene editing tools in future to modify and cure such diseases.

人体由数万亿个细胞组成。每个细胞的 DNA 中都包含编码新个体的信息。代码以基因的形式出现，其中包含制造特定蛋白质的信息，以及在不同组织和发育的不同时期打开和关闭基因的调节元件（称为增强子）。很难想象一根头发（60-70 微米）上可以排列 5 或 6 个细胞。 17 世纪第一台显微镜的研制使科学家们第一次看到了如此微小的结构。在接下来的 300 年里，显微镜的发展使我们现在可以可视化仅覆盖细胞直径千分之一（60-70 纳米）的子域。所谓的“超分辨率”显微镜现在使我们能够可视化增强子和基因如何相互作用以读取遗传密码，并且在过去的十年中，我们已经可以通过创建实时电影来可视化正在读取的代码。这种以如此高分辨率（称为纳米级）理解生物学的新方法已达到目前生物学研究的极限，因此建立非常容易理解的系统至关重要，使我们能够通过以下方式验证这些纳米级发现：将新结果与之前的模型位点分析进行比较。在我们的实验室中，我们研究编码α-珠蛋白的基因的表达，该基因有助于红细胞色素（血红蛋白）的合成。与几乎任何其他基因相比，这个基因如何打开和关闭可能更容易理解。我们已经证明，α基因是由五个增强子控制的，这些增强子作为一个集成单元，在打开目标基因时与其物理上接近。通过用荧光探针标记基因产生的 RNA，我们最近通过实时成像显示，当激活时，基因不会持续活跃，而是随着时间的推移而脉冲打开和关闭。这是基因表达调控的关键机制。在当前的提案中，我们正在研究这种机制，特别是询问它是否受到增强器的调节。我们将通过比较没有增强子的基因表达模式，然后如何通过以各种信息组合重新引入五个增强子来修改它来实现这一点。最后，我们将通过检查人类增强子的自然突变如何与受影响个体的红细胞变化相关来在临床背景下测试我们的发现。通过对基因调控的全面了解，我们的目标是找出基因通常如何打开和关闭、人类遗传疾病中基因如何受到干扰以及我们将来如何使用基因编辑工具来修改和治疗此类疾病。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A blood atlas of COVID-19 defines hallmarks of disease severity and specificity.

DOI：
10.1016/j.cell.2022.01.012
发表时间：
2022-03-03
期刊：
Cell
影响因子：
64.5
作者：
COvid-19 Multi-omics Blood ATlas (COMBAT) Consortium. Electronic address: julian.knight@well.ox.ac.uk;COvid-19 Multi-omics Blood ATlas (COMBAT) Consortium
通讯作者：
COvid-19 Multi-omics Blood ATlas (COMBAT) Consortium

Identification of Rare Loss-of-Function Genetic Variation Regulating Body Fat Distribution.

DOI：
10.1210/clinem/dgab877
发表时间：
2022-03-24
期刊：
The Journal of clinical endocrinology and metabolism
影响因子：
0
作者：
Koprulu M;Zhao Y;Wheeler E;Dong L;Rocha N;Li C;Griffin JD;Patel S;Van de Streek M;Glastonbury CA;Stewart ID;Day FR;Luan J;Bowker N;Wittemans LBL;Kerrison ND;Cai L;Lucarelli DME;Barroso I;McCarthy MI;Scott RA;Saudek V;Small KS;Wareham NJ;Semple RK;Perry JRB;O'Rahilly S;Lotta LA;Langenberg C;Savage DB
通讯作者：
Savage DB

Multipartite Super-Enhancers Function in an Orientation-Dependent Manner