The control of transcriptional corepressors by synaptic activity

突触活性对转录辅阻遏物的控制

• 批准号: BB/D011388/1
• 负责人: Giles Hardingham
• 金额: $ 36.02万
• 依托单位: University of Edinburgh
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2006
• 资助国家: 英国
• 起止时间: 2006 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FD011388%2F1
• 关键词: control; transcriptional; corepressors; synaptic; activity

Title: novel routes to the activation of gene transcription by synaptic activity: Brain cells (neurons) communicate with each other by releasing chemical messengers (neurotransmitters) onto each other at structures called synapses, a process called 'synaptic activity'. These messengers are detected by special channels on the cell surface, which then open and allows calcium and sodium ions to flow into the cell. This triggers the release of neurotransmitter onto yet more neurons. This means of neuron-to-neuron communication is the way by which information flows round the brain. However, 'synaptic activity' also triggers changes inside neurons. The calcium ions which flow into the neuron activate signal pathways, which in turn activate the transcription of genes. Transcription is a crucial step in the process whereby genes (made of DNA and located in the nucleus) are read by the cell's machinery and decoded into new proteins. These new proteins are crucial for many fundamental processes in the neuron. For example, learning and memory involves changes in the way neurons communicate with each other, and this process relies on these new proteins made in response to 'synaptic activity'. These new proteins also control how neurons in the brain develop from the foetus, through infancy and on to adulthood. Equally importantly, these new proteins also make individual neurons healthier and more likely to survive for longer than neurons that don't experience synaptic activity. Therefore, an understanding of how synaptic activity activates gene transcription is an important problem for scientists studying the brain. Our proposed research will characterise a completely new way by which genes can be activated by synaptic activity. The transcription of many genes is suppressed by special molecules called corepressors. One particularly important one is called SMRT, which represses many different genes in the nucleus by blocking the action of the cell's transcription machinery. We have recently discovered that when calcium ions flow into neurons following synaptic activity, signals in the neuron are activated which cause SMRT to leave the nucleus and go into the cytoplasm. Once in the cytoplasm, SMRT is unable to suppress transcription because the genes and transcription machinery are all in the nucleus. Therefore these genes become much easier to activate. Our work will uncover the exact signalling events that take place that make SMRT stop repressing transcription in the nucleus, and go into the cytoplasm. In addition, we will identify exactly what type of genes are likely to be influenced by this 'export' of SMRT. We will also determine the effect that SMRT export has on the way in which a neuron develops, looking particularly at the way a neuron changes shape as it matures. Because SMRT is known to repress the transcription of so many types of gene, signals that stop SMRT from working have the potential to have a big effect on the neuron. As mentioned earlier, the activation of gene transcription by synaptic activity controls many very important processes. SMRT export triggered by synaptic activity is a previously undiscovered route by which transcription of many genes can be turned on. Therefore understanding the mechanism and consequences of this process is of utmost importance. While this work is centred on the study of neurons, SMRT represses genes in many cell types, so the relevance of this work is not restricted to neurons. Furthermore, calcium ions don't just have effects in neurons, they are able to activate signalling pathways in all types of cell, from white blood cells to egg cells. The gene transcription that calcium ions activate in these cells are important for other processes, such as for white blood cells to fight infection. therefore our discoveries regarding how calcium activates gene transcription in neurons will be of benefit to scientists researching a wide variety of problems.

标题：通过突触活动激活基因转录的新途径：脑细胞（神经元）通过在称为突触的结构中相互释放化学信使（神经递质）来相互通信，这一过程称为“突触活动”。这些信使通过细胞表面的特殊通道进行检测，然后打开并允许钙和钠离子流入细胞。这会触发神经递质释放到更多的神经元上。这种神经元间的交流方式是信息在大脑中流动的方式。然而，“突触活动”也会引发神经元内部的变化。流入神经元的钙离子激活信号通路，进而激活基因的转录。转录是基因（由 DNA 组成并位于细胞核中）被细胞机器读取并解码为新蛋白质的过程中的关键步骤。这些新蛋白质对于神经元的许多基本过程至关重要。例如，学习和记忆涉及神经元相互交流方式的变化，而这个过程依赖于这些响应“突触活动”而产生的新蛋白质。这些新蛋白质还控制大脑神经元从胎儿、婴儿期一直到成年期的发育。同样重要的是，这些新蛋白质还使单个神经元比没有突触活动的神经元更健康，更有可能存活更长时间。因此，了解突触活动如何激活基因转录是研究大脑的科学家面临的一个重要问题。我们提出的研究将描述一种全新的方式，通过突触活动激活基因。许多基因的转录受到称为辅阻遏物的特殊分子的抑制。一种特别重要的方法称为 SMRT，它通过阻断细胞转录机制的作用来抑制细胞核中的许多不同基因。我们最近发现，当钙离子在突触活动后流入神经元时，神经元中的信号被激活，导致 SMRT 离开细胞核并进入细胞质。一旦进入细胞质，SMRT 就无法抑制转录，因为基因和转录机制都在细胞核中。因此这些基因变得更容易激活。我们的工作将揭示使 SMRT 停止抑制细胞核转录并进入细胞质的确切信号事件。此外，我们将准确确定哪些类型的基因可能会受到 SMRT 这种“输出”的影响。我们还将确定 SMRT 输出对神经元发育方式的影响，特别关注神经元成熟时形状变化的方式。由于 SMRT 已知会抑制多种基因的转录，因此阻止 SMRT 发挥作用的信号有可能对神经元产生重大影响。如前所述，突触活动激活基因转录控制着许多非常重要的过程。由突触活动触发的 SMRT 输出是一种以前未被发现的途径，通过该途径可以开启许多基因的转录。因此，了解这一过程的机制和后果至关重要。虽然这项工作的重点是神经元的研究，但 SMRT 会抑制许多细胞类型中的基因，因此这项工作的相关性并不局限于神经元。此外，钙离子不仅对神经元有影响，它们还能够激活从白细胞到卵细胞的所有类型细胞中的信号传导通路。钙离子在这些细胞中激活的基因转录对于其他过程很重要，例如白细胞抵抗感染。因此，我们关于钙如何激活神经元基因转录的发现将有利于科学家研究各种问题。

项目成果

In cortical neurons HDAC3 activity suppresses RD4-dependent SMRT export.

• DOI: 10.1371/journal.pone.0021056
• 发表时间: 2011
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Soriano FX;Hardingham GE
• 通讯作者: Hardingham GE

Role of histone acetylation in the activity-dependent regulation of sulfiredoxin and sestrin 2.

• DOI: 10.4161/epi.4.3.8753
• 发表时间: 2009-04-01
• 期刊: Epigenetics
• 影响因子: 3.7
• 作者: Soriano FX;Papadia S;Bell KF;Hardingham GE
• 通讯作者: Hardingham GE

Induction of sulfiredoxin expression and reduction of peroxiredoxin hyperoxidation by the neuroprotective Nrf2 activator 3H-1,2-dithiole-3-thione.

• DOI: 10.1111/j.1471-4159.2008.05648.x
• 发表时间: 2008-10
• 期刊: Journal of neurochemistry
• 影响因子: 4.7
• 作者: Soriano FX;Léveillé F;Papadia S;Higgins LG;Varley J;Baxter P;Hayes JD;Hardingham GE
• 通讯作者: Hardingham GE

Synaptic NMDA receptor activity boosts intrinsic antioxidant defenses.

• DOI: 10.1038/nn2071
• 发表时间: 2008-04
• 期刊: Nature neuroscience
• 影响因子: 25

Cellular Notch responsiveness is defined by phosphoinositide 3-kinase-dependent signals.

• DOI: 10.1186/1471-2121-7-10
• 发表时间: 2006-02-28
• 期刊: BMC cell biology
• 作者: McKenzie G;Ward G;Stallwood Y;Briend E;Papadia S;Lennard A;Turner M;Champion B;Hardingham GE
• 通讯作者: Hardingham GE