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，中枢神经系统）是由致力于干细胞的基础人群（神经干细胞（NSC）形成的。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（处理我们从外界收到的信息并控制行为的细胞），星形胶质细胞（为神经元提供支持的细胞）和少突胶质细胞（形成围绕神经元的绝缘脂肪髓鞘的细胞，以确保了快速的电动型电源电脑电气传播）。令人惊讶的是，所有NSC均具有相同的遗传物质（DNA），但它们产生了许多不同类型的神经元，在其生理特性和接线图上彼此不同，以及未知数的星形胶质细胞和少突胶质细胞亚型。这种细胞多样性如何从一组共同的前体中实现？控制NSC分化的关键机制（未成熟NSC的专业细胞产生）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集被“启用”或“闭合”分化细胞内。这些不同的基因集包含使细胞成为神经元，少突胶质细胞或星形胶质细胞的遗传程序。了解控制分化过程的表观遗传机制将为我们提供操纵NSC以形成特定细胞类型的可能性，这些细胞类型可能是神经系统疾病的未来基于干细胞的治疗所必需的，例如多发性硬化症，损伤，中风和其他神经变性条件。我们最近发现了一种新型蛋白质，称为Schwann细胞因子1（SC1或PRDM4），该因子是发展NSC中基因表达的表观遗传调节剂。必须降低SC1的水平，以使分化开始。因此，SC1可能为直接分化NSC提供了新的目标。但是，我们首先需要了解SC1的活动如何促进体内发展。我们发现SC1与另一种蛋白质PRMT5结合并起作用，该酶是一种以不寻常的方式修饰染色质（DNA及其蛋白质包装器的复合物）的酶。这为我们提供了一个开始，以开始阐明SC1的作用机理：PRMT5复合物及其生物学后果。最终，我们希望获得有关如何在重新编程NSC中使用SC1：PRMT5的信息，以采用特定的细胞命运进行细胞替代疗法。

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