Histone arginine methylation and the control of neural stem cell proliferation and differentiation.

组蛋白精氨酸甲基化与神经干细胞增殖和分化的控制。

• 批准号: BB/J006602/1
• 负责人: William Richardson
• 金额: $ 62.89万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 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=BB%2FJ006602%2F1
• 关键词: Histone; arginine; methylation; control; neural

The central nervous system (brain and spinal cord, CNS) is formed from a founding population of committed stem cells, the neural stem cells (NSCs). These cells give rise to the three major cell types of the CNS: neurons (cells that process the information we receive from the outside world and control our behaviour), astrocytes (cells that provide support to the neurons) and oligodendrocytes (cells that form the insulating fatty myelin sheath around the neurons that ensures rapid electrical transmission of electrical impulses). Amazingly, all NSCs are endowed with identical genetic material (DNA), yet they generate many different types of neurons, distinct from each other in their physiological properties and wiring diagram, as well as an unknown number of astrocyte and oligodendrocyte subtypes. How is such cellular diversity achieved from a common set of precursors? The key mechanisms that control NSC differentiation (the generation of specialized cells from immature NSCs) are referred to as epigenetic mechanisms. Such mechanisms do not change the genetic material within the cells, but rather ensure that the right sets of genes are turned "on" or kept "off" within the differentiated cells. These different gene sets comprise the genetic programs that make the cell a neuron, oligodendrocyte or astrocyte. Understanding the epigenetic mechanisms that govern the process of differentiation will provide us with the possibility of manipulating NSCs to form specific cell types that may be required for future stem cell-basedtherapies for neurological diseases - e.g. multiple sclerosis, injury, stroke and other neuro-degenerative conditions. We have recently discovered a novel protein, called Schwann cell factor 1 (SC1 or PRDM4) which is an epigenetic regulator of gene expression in developing NSCs. The levels of SC1 must be lowered in order for differentiation to begin. Therefore, SC1 might provide a novel target to direct differentiation of NSCs. However, we first need to understand how the activity of SC1 contributes to development in vivo. We found that SC1 binds to and acts in partnership with another protein, PRMT5, which is an enzyme that modifies chromatin (the complex of DNA and its protein wrapper) in an unusual way. This gives us a handle to start unravelling the mechanism of action of the SC1:PRMT5 complex and its biological consequences. Ultimately, we hope to gain information on how SC1:PRMT5 might be used in re-programming NSCs to adopt specific cell fates for cell replacement therapies.

中枢神经系统（脑和脊髓，CNS）由定向干细胞（神经干细胞（NSC））的创始群体形成。这些细胞产生了中枢神经系统的三种主要细胞类型：神经元（处理我们从外界接收的信息并控制我们行为的细胞），星形胶质细胞（为神经元提供支持的细胞）和少突胶质细胞（在神经元周围形成绝缘脂肪髓鞘的细胞，确保电脉冲的快速电传输）。令人惊讶的是，所有的神经干细胞都具有相同的遗传物质（DNA），但它们产生许多不同类型的神经元，在生理特性和接线图上彼此不同，以及数量未知的星形胶质细胞和少突胶质细胞亚型。这种细胞多样性是如何从一组共同的前体中获得的？控制NSC分化的关键机制（从未成熟的NSC产生特化细胞）被称为表观遗传机制。这种机制不会改变细胞内的遗传物质，而是确保正确的基因组在分化的细胞内被“打开”或保持“关闭”。这些不同的基因组组成了使细胞成为神经元、少突胶质细胞或星形胶质细胞的遗传程序。了解支配分化过程的表观遗传机制将为我们提供操纵NSC形成特定细胞类型的可能性，这些细胞类型可能是未来神经系统疾病（例如多发性硬化症、损伤、中风和其他神经退行性疾病）基于干细胞的治疗所需的。我们最近发现了一种新的蛋白质，称为雪旺细胞因子1（SC1或PRDM4），它是发育中的神经干细胞中基因表达的表观遗传调节因子。必须降低SC 1的水平，以便分化开始。因此，SC1可能为神经干细胞的定向分化提供新的靶点。然而，我们首先需要了解SC1的活性如何促进体内发育。我们发现SC1与另一种蛋白质PRMT5结合并与其合作，PRMT5是一种以不寻常的方式修饰染色质（DNA及其蛋白质包装物的复合物）的酶。这给了我们一个开始解开SC1：PRMT5复合物的作用机制及其生物学后果的把手。最终，我们希望获得有关SC1：PRMT5如何用于重新编程NSC以采用特定细胞命运进行细胞替代疗法的信息。

项目成果

Zinc fingers 1, 2, 5 and 6 of transcriptional regulator, PRDM4, are required for its nuclear localisation.

转录调节因子 PRDM4 的锌指 1、2、5 和 6 是其核定位所必需的。

• DOI: 10.1016/j.bbrc.2016.04.128
• 发表时间: 2016
• 期刊: Biochemical and biophysical research communications
• 影响因子: 3.1
• 作者: Tunbak H

Temporal correlation of elevated PRMT1 gene expression with mushroom body neurogenesis during bumblebee brain development

• DOI: 10.1101/449116
• 发表时间: 2018-10
• 期刊: bioRxiv
• 作者: Cui Guan;M. Egertová;Clint J. Perry;L. Chittka;A. Chittka

Differential regulation of SC1/PRDM4 and PRMT5 mediated protein arginine methylation by the nerve growth factor and the epidermal growth factor in PC12 cells.

• DOI: 10.1016/j.neulet.2013.06.051
• 发表时间: 2013-08-29
• 期刊: Neuroscience letters
• 影响因子: 2.5
• 作者: Chittka A

Evolution of the CNS myelin gene regulatory program.

• DOI: 10.1016/j.brainres.2015.10.013
• 发表时间: 2016-06-15
• 期刊: Brain research
• 影响因子: 2.9
• 作者: Li H;Richardson WD
• 通讯作者: Richardson WD

Identification of Prdm genes in human corneal endothelium.

• DOI: 10.1016/j.exer.2017.02.009
• 发表时间: 2017-06
• 期刊: Experimental eye research
• 影响因子: 3.4
• 作者: Rolev K;O'Donovan DG;Georgiou C;Rajan MS;Chittka A
• 通讯作者: Chittka A