Transcriptional control of cell fate decisions by chromatin remodelling proteins

染色质重塑蛋白对细胞命运决定的转录控制

• 批准号: MR/R009759/1
• 负责人: Brian Hendrich
• 金额: $ 96.6万
• 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: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FR009759%2F1
• 关键词: Transcriptional; control; cell; fate; decisions

A cell's identity is defined by its genes. A cell located in the heart, for example, will express heart genes, but not genes important for liver or brain function. Conversely, liver cells express liver genes but not heart or lung genes. During embryonic development animals are formed by different groups of stem cells, which are able to give rise to the myriad of different cell types found in an adult organism. When stem cells undergo the process of differentiating into a new cell type, it is critically important that they turn on genes appropriate for the new cell type, but also turn off the genes that define a 'stem cell' identity and also keep off any genes associated with other cell types. Failure to properly regulate expression of all these different kinds of genes can result in the wrong decisions being made, or the inability to make any decision when required. The consequences of such failure can be developmental abnormalities or cancer. Unsurprisingly, then, our cells contain many proteins whose jobs are to ensure the proper control of gene expression. This proposal focusses on two such proteins, called Chd4 and Brg1. These proteins control the way genes get packaged within the cell. Though at a mechanistic level these two proteins appear to have similar activities, a number of studies have found that they actually tend to work in opposition. We know that loss of either protein results in failed development from very early stages, and both proteins are often found to be deleted or mutated in cancer. We propose that it is precisely this balance of opposing activities between Chd4 and Brg1 that fine tunes gene expression patterns, and that this balance is crucial for cells to successfully make developmental decisions. Yet exactly how the biochemical activities of these proteins controls gene expression, and whether the two really directly control the expression of the same genes during development is not well understood. In the work proposed herein we will use cutting edge technologies to very accurately define the function of these proteins in stem cells and in early embryonic cells as they make their very first decisions. We will show how loss of one either protein impacts the function of other key regulatory proteins, and how this leads to developmental failure. We will then examine how these proteins function during the very first cell fate decision in mammalian embryogenesis. Together this project will reveal how gene expression is controlled as cells make decisions, and how the cells use these proteins to precisely control cell fate choices during normal development. This will inform the creation of new methods for controlling gene expression in mammalian cells. Such methods could be of considerable benefit in efforts to prevent the progression of cancer, and to enable more efficient and effective protocols to use stem cells in regenerative medicine.

细胞的特性是由它的基因决定的。例如，位于心脏的细胞将表达心脏基因，但不表达对肝脏或大脑功能重要的基因。相反，肝细胞表达肝脏基因，但不表达心脏或肺基因。在胚胎发育过程中，动物由不同的干细胞组组成，这些干细胞能够产生在成年生物体中发现的无数不同类型的细胞。当干细胞经历分化为新细胞类型的过程时，至关重要的是它们打开了适合新细胞类型的基因，但同时也关闭了定义“干细胞”身份的基因，并阻止了任何与其他细胞类型相关的基因。未能适当地调控所有这些不同类型的基因的表达可能会导致做出错误的决定，或者在需要时无法做出任何决定。这种失败的后果可能是发育异常或癌症。因此，毫不奇怪，我们的细胞含有许多蛋白质，它们的工作是确保适当地控制基因表达。这项提议关注的是两种这样的蛋白质，分别是CHD4和BRG1。这些蛋白质控制着基因在细胞内包装的方式。尽管这两种蛋白质在机械学水平上似乎具有相似的活动，但许多研究发现，它们实际上往往是相反的。我们知道，这两种蛋白质中的任何一种的丢失都会导致早期发育失败，而在癌症中，这两种蛋白质经常被发现是缺失或突变的。我们认为，正是CHD4和BRG1之间相反活动的这种平衡微调了基因表达模式，并且这种平衡对于细胞成功地做出发育决定是至关重要的。然而，这些蛋白质的生化活动究竟是如何控制基因表达的，以及这两种蛋白质是否真的在发育过程中直接控制相同基因的表达，还不是很清楚。在这里提出的工作中，我们将使用尖端技术非常准确地定义这些蛋白质在干细胞和早期胚胎细胞中的功能，因为它们做出了最初的决定。我们将展示其中一种蛋白的缺失如何影响其他关键调控蛋白的功能，以及这如何导致发育失败。然后，我们将研究这些蛋白质在哺乳动物胚胎发育的第一个细胞命运决定过程中如何发挥作用。这一项目将揭示细胞在做出决定时如何控制基因表达，以及细胞如何使用这些蛋白质来精确控制正常发育期间的细胞命运选择。这将为控制哺乳动物细胞中基因表达的新方法的创造提供信息。这些方法可能在努力防止癌症进展方面有相当大的好处，并使再生医学中使用干细胞的更有效和更有效的方案成为可能。

项目成果

The Nucleosome Remodelling and Deacetylation complex coordinates the transcriptional response to lineage commitment in pluripotent cells

核小体重塑和脱乙酰化复合物协调多能细胞中谱系定型的转录反应

• DOI: 10.1101/2023.02.09.527610
• 发表时间: 2023
• 作者: Montibus B

Enhancer-promoter interactions are reconfigured through the formation of long-range multiway chromatin hubs as mouse ES cells exit pluripotency

• DOI: 10.1101/2023.02.08.527615
• 发表时间: 2023-02
• 期刊: bioRxiv
• 作者: D. Lando;X. Ma;Y. Cao;A. Jartseva;T. Stevens;W. Boucher;N. Reynolds;B. Montibus;D. Hall;A. Lackner;R. Ragheb;M. Leeb;B. Hendrich;E. Laue

The Nucleosome Remodelling and Deacetylation complex coordinates the transcriptional response to lineage commitment in pluripotent cells.

核小体重塑和脱乙酰化复合物协调多能细胞中对谱系定型的转录反应。

• DOI: 10.17863/cam.104622
• 发表时间: 2023
• 作者: Montibus B