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Cell-Specific PRC1 Accessory Proteins and the Regulation of Mammalian Neurodevelopment

细胞特异性 PRC1 辅助蛋白和哺乳动物神经发育的调节

基本信息

批准号：
MR/S007644/1
负责人：
Robert Illingworth
金额：
$ 153.37万
依托单位：
University of Edinburgh
依托单位国家：
英国
项目类别：
Fellowship
财政年份：
2019
资助国家：
英国
起止时间：
2019 至无数据
项目状态：
未结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FS007644%2F1
关键词：
Cell Specific PRC1 Accessory Proteins

项目摘要

Mammalian embryonic development is the process whereby a single naïve cell is expanded, and serially specialised, to produce all of the functional cell types of the adult body. This intricate process is governed by proteins, which bind to regulatory DNA sequences and establish the appropriate temporal and spatial patterns of gene expression. One such family of protein effectors form multi-subunit-assemblies termed polycomb repressive complexes (PRCs), which function to block gene expression by chemically and physically modifying chromatin - the packaged form of DNA. In the developing brain, changes in cell state occur as progenitor cells proliferate, migrate and specialise, and PRCs have been shown to be important for these steps. Consequently, loss of PRC function in this context leads to cellular and structural abnormalities. Weaver syndrome, a disorder characterised by cognitive impairment and often brain overgrowth, is caused by the loss of PRC function. Moreover, mutations that block PRC activity occur in the majority of cases of diffuse intrinsic pontine glioma (DIPG) in which they promote tumour formation. PRCs are also required for the regulation of cell proliferation, specialisation and protection against neurodegeneration in the adult brain. Mechanistic interpretation of these cellular and structural abnormalities, however, is hindered by the lack of understanding of how PRCs regulate neurodevelopmental gene expression patterns. Filling this knowledge gap is key to understanding not only the molecular basis of brain development, but also in determining the underlying deficits in developmental brain disorders. To this end, it is important to determine the molecular mechanics of PRC function and targeting during neurodevelopment. My key aims are: 1). Determine the extent and functional importance of alterations in PRC complex composition during neurodevelopment. 2). Identify and manipulate proteins which act either directly, or in collaboration with chromatin modifications, to recruit PRCs to their target genes during neurodevelopment. To address these aims I will utilise artificially differentiated and primary cultured neural progenitor cells (NPCs) in conjunction with high-throughput analysis of chromatin state, quantitative analysis of protein composition of PRC bound chromatin, genome-engineering and synthetic protein targeting approaches. A complete understanding of the molecular basis of disorders of the brain which arise from PRC dysfunction will be critical as a step towards establishing effective and safe therapeutic approaches, prognostic and diagnostic tests and to inform clinical support.

哺乳动物胚胎发育是单个幼稚细胞扩增并连续特化以产生成体所有功能细胞类型的过程。这个复杂的过程是由蛋白质控制的，蛋白质与调控DNA序列结合，建立适当的基因表达的时空模式。一个这样的蛋白质效应子家族形成称为多梳抑制复合物（PRCs）的多亚基组装体，其功能是通过化学和物理修饰染色质（DNA的包装形式）来阻断基因表达。在发育中的大脑中，随着祖细胞增殖、迁移和特化，细胞状态发生变化，而PRCs已被证明对这些步骤很重要。因此，在这种情况下，PRC功能的丧失导致细胞和结构异常。韦弗综合征是一种以认知障碍和大脑过度生长为特征的疾病，是由PRC功能丧失引起的。此外，阻断PRC活性的突变发生在弥漫性内在脑桥胶质瘤（DIPG）的大多数病例中，其中它们促进肿瘤形成。PRCs也需要调节细胞增殖，专业化和保护成人大脑免受神经变性。然而，这些细胞和结构异常的机制解释，阻碍了缺乏了解PRCs如何调节神经发育基因的表达模式。填补这一知识空白不仅是理解大脑发育的分子基础的关键，也是确定发育性大脑障碍的潜在缺陷的关键。为此，重要的是要确定PRC功能和靶向在神经发育过程中的分子力学。我的主要目标是：1）。确定在神经发育过程中PRC复合物组成的改变的程度和功能重要性。2）。识别和操纵蛋白质，这些蛋白质直接或与染色质修饰合作，在神经发育过程中将PRC招募到其靶基因。为了实现这些目标，我将利用人工分化和原代培养的神经祖细胞（NPC）结合染色质状态的高通量分析，PRC结合染色质的蛋白质组成的定量分析，基因组工程和合成蛋白质靶向方法。对PRC功能障碍引起的脑疾病的分子基础的全面理解将是建立有效和安全的治疗方法，预后和诊断测试的关键一步，并为临床支持提供信息。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

DAXX safeguards heterochromatin formation in embryonic stem cells

DOI：
10.1101/2021.04.28.441827
发表时间：
2021-04
期刊：
bioRxiv
影响因子：
0
作者：
Antoine Canat;Adeline Veillet;Renaud Batrin;Clara Dubourg;Robert S. Illingworth;E. Fabre;Pierre Therizols-Pie
通讯作者：
Antoine Canat;Adeline Veillet;Renaud Batrin;Clara Dubourg;Robert S. Illingworth;E. Fabre;Pierre Therizols-Pie

RINGs, DUBs and Abnormal Brain Growth-Histone H2A Ubiquitination in Brain Development and Disease.

DOI：
10.3390/epigenomes6040042
发表时间：
2022-12-02
期刊：
EPIGENOMES
影响因子：
2.5
作者：
Doyle, Lucy Anne;Unlu Bektas, Firuze;Chatzantonaki, Eleftheria;Repton, Charlotte;Derrien, Alexandra;Illingworth, Robert Scott
通讯作者：
Illingworth, Robert Scott

DAXX safeguards heterochromatin formation in embryonic stem cells.

DAXX 保护胚胎干细胞中异染色质的形成。