Deciphering the mechanism through which BRD4 mutations contribute to the neurodevelopmental disorder

破译 BRD4 突变导致神经发育障碍的机制

• 批准号: MR/X008479/1
• 负责人: Pradeepa Madapura-Marulasiddappa
• 金额: $ 96.75万
• 依托单位: Queen Mary University of London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FX008479%2F1
• 关键词: Deciphering; mechanism; through; BRD4; mutations

Epigenetic proteins, including writers and readers of histone posttranslational modifications and chromatin remodelling proteins, play an essential role in the controlled tissue-specific regulation of gene expression. Acetylation of histone lysines is one of the most abundant modifications which alters chromatin structure and function. A delicate balance between lysine acetylation and deacetylation is essential for the normal functioning of the central nervous system. Gene mutations that perturb the histone acetylation pathway cause many neurodevelopmental disorders, warranting detailed investigation into the specific role of the acetylation pathway in the central nervous system. Recently we have discovered that mutations in gene encoding histone acetylation reader protein BRD4 lead to a neurodevelopmental disorder. However, it is not clear how mutations in this gene encoding epigenetic factor lead to specific neurodevelopmental disorders. We aim to investigate how mutations in BRD4 cause altered development and functioning of the central nervous system. We will first identify genes regulated by BRD4 in human neuronal cell types. We will then identify neuronal-specific enhancers regulated by BRD4 and link these enhancers to target genes that are dysregulated upon depletion or mutation in BRD4. Next, we will investigate how patient-specific mutations in BRD4 cause an altered transcriptional programme by performing single-cell transcriptomics and epigenetic alterations in the mini-brain organoid model. Furthermore, we will test the efficacy of epigenetic drugs in rescuing the altered brain development phenotype and functioning due to BRD4 mutations. Overall, this proposal aims to uncover the role of BRD4 in human brain development and function and how BRD4 mutations lead to specific neurodevelopmental disorders.

表观遗传蛋白，包括组蛋白翻译后修饰的编写者和读者以及染色质重塑蛋白，在基因表达的受控组织特异性调节中发挥着重要作用。组蛋白赖氨酸的乙酰化是改变染色质结构和功能的最丰富的修饰之一。赖氨酸乙酰化和脱乙酰化之间的微妙平衡对于中枢神经系统的正常功能至关重要。扰乱组蛋白乙酰化途径的基因突变会导致许多神经发育障碍，需要对乙酰化途径在中枢神经系统中的具体作用进行详细研究。最近我们发现编码组蛋白乙酰化阅读器蛋白 BRD4 的基因突变会导致神经发育障碍。然而，目前尚不清楚这种编码表观遗传因子的基因突变如何导致特定的神经发育障碍。我们的目标是研究 BRD4 突变如何导致中枢神经系统的发育和功能改变。我们将首先鉴定人类神经细胞类型中受 BRD4 调节的基因。然后，我们将鉴定受 BRD4 调节的神经元特异性增强子，并将这些增强子与 BRD4 缺失或突变时失调的靶基因联系起来。接下来，我们将通过在微型脑类器官模型中进行单细胞转录组学和表观遗传改变，研究 BRD4 中患者特异性突变如何导致转录程序改变。此外，我们将测试表观遗传药物在挽救因 BRD4 突变而改变的大脑发育表型和功能方面的功效。总体而言，该提案旨在揭示 BRD4 在人类大脑发育和功能中的作用以及 BRD4 突变如何导致特定的神经发育障碍。