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。每个单元格在其DNA中包含信息，以编码一个新个体。该代码以包含信息的基因形式出现，并在不同组织中以及在开发的不同时间中开关基因开关的基因开关和关闭基因的调节元素（称为增强剂）。很难想象一个人可以将5或6个细胞排成人的头发（60-70微米）。 17世纪首批显微镜的发展使科学家能够第一次看到这样的微小结构。在接下来的300年中，已经开发了显微镜，因此我们现在可以看到仅遍布细胞直径（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代码，并且在过去的十年中，可以通过创建实时电影来可视化所读取的代码。这种新的理解生物学的新方法被称为纳米级，这是研究生物学目前可能的可能性的局限性，因此，建立良好理解的系统使我们能够通过将新的纳米级发现与先前的模型分析进行比较，这是至关重要的。在我们的实验室中，我们研究了编码α-珠蛋白的基因的表达，该基因有助于合成红细胞色素（血红蛋白）。如何打开和关闭该基因可能几乎可以理解几乎所有其他基因。我们已经表明，α基因由五个增强子控制，这些增强子充当一个集成单元，它们在打开其时与其靶基因相邻。通过将基因产生的RNA用荧光探针标记，我们最近通过实时成像显示，当被激活时，基因不是连续的活性，而是随着时间的推移而开或关闭的脉冲。这是基因表达调节的基础的关键机制。在当前的提案中，我们正在研究这种机制，尤其是询问它是否受增强剂的调节。我们将通过比较没有增强子的基因表达模式来做到这一点，然后如何通过重新引入各种信息组合中的五个增强子来修改它。最后，我们将通过研究人类增强子的自然突变与受影响个体的红细胞的变化如何相关，以测试我们的发现。通过对基因调节的完全了解，我们旨在找出通常如何打开和关闭基因，如何在人类遗传疾病中扰动这一点，以及我们将来如何使用基因编辑工具来修饰和治愈此类疾病。

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