CONTROL OF OLIGODENDROCYTE DEVELOPMENT BY OLIG2 AND CHROMATIN REMODELLING COMPLEXES

OLIG2 和染色质重塑复合物对少突胶质细胞发育的控制

• 批准号: BB/S008934/1
• 负责人: William Richardson
• 金额: $ 64.43万
• 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: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FS008934%2F1
• 关键词: CONTROL; OLIGODENDROCYTE; DEVELOPMENT; OLIG2; CHROMATIN

Amazingly, the thousands of different cell types that make up our body - blood cells, muscle cells, nerve cells, for example - all develop from the same single cell, the fertilized egg. Hence, all cell types contain the same DNA, yet each contains a set of specialized proteins that are unique to that particular cell type, on top of a core set of "housekeeping" proteins found in all cells. The "cell-type-specific" proteins are what give a cell its particular identity - what defines it as a blood cell or nerve cell, for example. Examples are haemoglobin (present or "expressed" only in red blood cells), keratin (only in skin cells), insulin (only in pancreatic cells) and so on. How are these characteristic proteins expressed in only one or a few cell types despite the fact that all cells contain the same DNA - the same collection of genes? If we could understand the mechanisms that keep some genes shut down and others highly expressed, we might learn how to convert one cell type into another - for example, to cure diseases in which a particular type of cell is damaged or destroyed. Examples of such diseases are type-one diabetes, in which the pancreatic cells that make insulin are destroyed by the immune system, or motor neuron disease, in which spinal neurons that control muscle movement die for unknown reasons. If we could manufacture replacement cells from healthy cells in the body, or in a dish, this could be extremely helpful.There are many proteins in cells whose function is purely to activate or repress other protein-coding genes, by binding specific DNA sequences next to those genes. Such DNA-binding proteins are called "transcription factors" because they control whether a given gene is "transcribed" into the instructions for assembling the corresponding protein. For example, the transcription factor OLIG2 is present uniquely in cells in the central nervous system called "oligodendrocytes". These cells make "myelin", spiral wraps of insulating membrane around "axons", the long thin extensions of nerve cells that carry electrical impulses from one part of the brain to another. This greatly increases the speed at which information travels around the brain. Without myelin, we literally would not be able to think quickly, or at all! Moreover, when myelin is damaged, as it is during the demyelinating disease multiple sclerosis, nervous function can be seriously compromised. We therefore want to understand how OLIG2 can activate myelin-forming genes uniquely in oligodendrocytes.DNA in chromosomes ("chromatin") is normally tightly wound into a form that makes its encoded information inaccessible. Transcription factors like OLIG2 cannot by themselves unravel the DNA - they need to interact with many other proteins to form large "chromatin remodelling complexes" that can together release a gene from its tightly folded, "closed" state. These complexes are of several types (e.g. INO80 and ISWI complexes) whose individual functions are poorly understood. We recently found that OLIG2 is associated tightly with both of these complexes and others, raising the question of why different complexes are needed, and what do they individually do?Our hypothesis is that the different chromatin remodelling complexes come into play at different stages of oligodendrocyte development to activate different sets of genes that allow progression along the path from early embryonic stem cell to fully mature, myelin-forming oligodendrocyte. Our project will test this idea by identifying the genes associated with the INO80 and ISWI complexes, determining whether and how OLIG2 directs the INO80 and ISWI complexes to those genes and whether different sets of genes are engaged as oligodendrocytes develop. Our experiments will help to illuminate general mechanisms of transcriptional regulation, applicable to all cell types, as well as helping us understand the detailed workings of the mammalian brain.

令人惊讶的是，组成我们身体的数千种不同细胞类型-血细胞，肌肉细胞，神经细胞，例如-都是从同一个单细胞-受精卵发展而来的。因此，所有细胞类型都含有相同的DNA，但每种细胞类型都含有一组特定的蛋白质，这些蛋白质是该特定细胞类型所特有的，在所有细胞中发现的一组核心“管家”蛋白质之上。“细胞类型特异性”蛋白质赋予细胞特定的身份-例如，将其定义为血细胞或神经细胞。例如血红蛋白（仅存在于或“表达”于红细胞中）、角蛋白（仅存在于皮肤细胞中）、胰岛素（仅存在于胰腺细胞中）等。尽管所有细胞都含有相同的DNA --相同的基因集合，但这些特征性蛋白质是如何仅在一种或几种细胞类型中表达的？如果我们能够理解使某些基因关闭而另一些基因高度表达的机制，我们就可能学会如何将一种细胞类型转化为另一种细胞类型--例如，治愈某种特定类型细胞受损或被破坏的疾病。这类疾病的例子是1型糖尿病，其中制造胰岛素的胰腺细胞被免疫系统破坏，或运动神经元疾病，其中控制肌肉运动的脊髓神经元因未知原因死亡。如果我们能从体内或培养皿中的健康细胞中制造出替代细胞，这将是非常有帮助的。细胞中有许多蛋白质，它们的功能纯粹是激活或抑制其他蛋白质编码基因，通过结合这些基因旁边的特定DNA序列。这种DNA结合蛋白被称为“转录因子”，因为它们控制给定的基因是否被“转录”成组装相应蛋白质的指令。例如，转录因子0 LIG 2独特地存在于中枢神经系统中称为“少突胶质细胞”的细胞中。这些细胞制造“髓磷脂”，螺旋状包裹在“轴突”周围的绝缘膜，轴突是神经细胞的细长延伸，将电脉冲从大脑的一个部分传递到另一个部分。这大大提高了信息在大脑中传播的速度。如果没有髓磷脂，我们就无法快速思考，甚至根本无法思考！此外，当髓鞘受损时，就像多发性硬化症脱髓鞘疾病期间一样，神经功能可能会严重受损。因此，我们想了解OLIG 2是如何在少突胶质细胞中独特地激活髓鞘形成基因的。染色体中的DNA（“染色质”）通常被紧密缠绕成一种使其编码信息无法访问的形式。像OLIG 2这样的转录因子本身不能解开DNA -它们需要与许多其他蛋白质相互作用以形成大的“染色质重塑复合物”，这些复合物可以一起将基因从其紧密折叠的“闭合”状态释放出来。这些复合物有几种类型（如INO 80和ISWI复合物），其各自的功能知之甚少。我们最近发现OLIG 2与这些复合物和其他复合物紧密相关，这就提出了为什么需要不同的复合物以及它们各自起什么作用的问题。我们的假设是，不同的染色质重塑复合物在少突胶质细胞发育的不同阶段发挥作用，激活不同的基因组，使其沿着从早期胚胎干细胞到完全成熟的髓鞘形成少突胶质细胞的路径发展。我们的项目将通过鉴定与INO 80和ISWI复合物相关的基因来测试这一想法，确定OLIG 2是否以及如何将INO 80和ISWI复合物导向这些基因，以及是否有不同的基因组参与少突胶质细胞的发育。我们的实验将有助于阐明转录调控的一般机制，适用于所有细胞类型，以及帮助我们了解哺乳动物大脑的详细工作。

项目成果

Structural and Lipidomic Alterations of Striatal Myelin in 16p11.2 Deletion Mouse Model of Autism Spectrum Disorder.

自闭症谱系障碍 16p11.2 缺失小鼠模型中纹状体髓磷脂的结构和脂质组学改变

• DOI: 10.3389/fncel.2021.718720
• 发表时间: 2021
• 期刊: Frontiers in cellular neuroscience
• 影响因子: 5.3
• 作者: Ju J;Yang X;Jiang J;Wang D;Zhang Y;Zhao X;Fang X;Liao H;Zheng L;Li S;Hou ST;Liang L;Pan Y;Li H;Li N
• 通讯作者: Li N

Life-long oligodendrocyte development and plasticity.

• DOI: 10.1016/j.semcdb.2021.02.004
• 发表时间: 2021-08
• 期刊: Seminars in cell & developmental biology
• 影响因子: 7.3
• 作者: Nishiyama A;Shimizu T;Sherafat A;Richardson WD
• 通讯作者: Richardson WD

Generation of Chicken IgY against SARS-COV-2 Spike Protein and Epitope Mapping.

• DOI: 10.1155/2020/9465398
• 发表时间: 2020
• 期刊: Journal of immunology research
• 影响因子: 4.1
• 作者: Lu Y;Wang Y;Zhang Z;Huang J;Yao M;Huang G;Ge Y;Zhang P;Huang H;Wang Y;Li H;Wang W
• 通讯作者: Wang W

Chemical approach to generating long-term self-renewing pMN progenitors from human embryonic stem cells.

• DOI: 10.1093/jmcb/mjab076
• 发表时间: 2022-02-24
• 期刊: Journal of molecular cell biology
• 影响因子: 5.5
• 作者: Zhang GY;Lv ZM;Ma HX;Chen Y;Yuan Y;Sun PX;Feng YQ;Li YW;Lu WJ;Yang YD;Yang C;Yu XL;Wang C;Liang SL;Zhang ML;Li HL;Li WL
• 通讯作者: Li WL