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，例如，成千上万种构成我们身体的不同细胞类型 - 例如，血细胞，肌肉细胞，神经细胞 - 都来自同一单细胞，受精卵。因此，所有细胞类型都包含相同的DNA，但是每种细胞类型都包含一组专门的蛋白质，这些蛋白质是该特定细胞类型所独有的，在所有细胞中发现的“家具”蛋白质的核心集中。 “细胞型特异性”蛋白是使细胞具有特定身份的原因 - 例如，将其定义为血细胞或神经细胞。例如血红蛋白（仅在红细胞中或“表达”），角蛋白（仅在皮肤细胞中），胰岛素（仅在胰腺细胞中）等。尽管所有细胞都包含相同的DNA - 相同的基因集合，但这些特征蛋白如何仅以一种或几种细胞类型表达？如果我们能够理解使某些基因关闭并高度表达的机制，那么我们可能会学习如何将一种细胞类型转换为另一种细胞类型 - 例如，治愈特定类型的细胞受损或破坏的疾病。此类疾病的例子是一种糖尿病，其中使胰岛素被免疫系统或运动神经元疾病破坏的胰腺细胞，其中控制肌肉运动的脊柱神经元死于原因是未知的原因。如果我们可以从体内健康细胞或菜肴中生产替代细胞，这可能非常有用。细胞中有许多蛋白质通过结合这些基因旁边的特定DNA序列，其功能纯粹可以激活或抑制其他蛋白质编码基因。这种DNA结合蛋白被称为“转录因子”，因为它们控制给定基因是否“转录”到组装相应蛋白质的指令中。例如，转录因子olig2在中枢神经系统中唯一存在称为“少突胶质细胞”的细胞。这些细胞形成了“髓磷脂”，螺旋形成了围绕“轴突”的绝缘膜，这是神经细胞的长薄延伸，这些神经细胞的较薄延伸，将电脉冲从大脑的一部分到另一部分。这大大提高了信息在大脑周围传播的速度。没有髓鞘，我们实际上将无法快速思考或根本无法思考！此外，当髓磷脂受损时，就像脱髓鞘疾病多发性硬化症一样，神经功能可能会严重损害。因此，我们想了解Olig2如何在少突胶质细胞中唯一激活髓磷脂形成基因。染色体中的DNA（“染色质”）通常会紧紧缠绕成一种使其编码信息无法访问的形式。诸如Olig2之类的转录因子本身不能揭开DNA - 它们需要与许多其他蛋白质相互作用，以形成大型的“染色质重塑复合物”，从而可以将基因从其紧密折叠的“封闭”状态中释放出来。这些复合物具有几种类型（例如INO80和ISWI复合物），其各个功能对知识很少。 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.我们的项目将通过识别与INO80和ISWI复合物相关的基因来测试这一想法，从而确定OLIG2是否以及如何将INO80和ISWI复合物引导到这些基因以及是否随着少突胶质细胞的发展而参与不同的基因。我们的实验将有助于阐明适用于所有细胞类型的转录调控的一般机制，并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

The INO80 chromatin remodeling complex regulates histone H2A.Z mobility and the G1-S transition in oligodendrocyte precursors

• DOI: 10.1101/2024.01.09.574847
• 发表时间: 2024-01-09
• 期刊: bioRxiv
• 作者: Wright，J. L.;Jiang，Y.;Richardson，W. D.
• 通讯作者: Richardson，W. D.

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

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