Investigating convergent gene expression and neuronal activity phenotypes in human and mouse neurons caused by depletion and mutation of mental disease-associated chromatin regulators

研究由精神疾病相关染色质调节因子的耗竭和突变引起的人类和小鼠神经元的趋同基因表达和神经元活动表型

• 批准号: 504019642
• 负责人: Dr. Moritz Mall
• 金额: --
• 依托单位: Nachwuchsgruppe Engineering von Zellidentitäten und Krankheitsmodellen
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/504019642?language=en
• 关键词: Investigating; convergent; gene; expression; neuronal

Mental disorders, such as autism and schizophrenia, are highly prevalent and are a huge health burden. They can be diverse and have multifactorial genetic origins, yet they often result in overlapping cognitive, social and molecular phenotypes. While mutations in synaptic components can mechanistically explain impaired neuronal function in patients, emerging evidence highlights involvement of several chromatin regulators in mental disorders. However, the underlying molecular mechanisms by which mutations of chromatin regulators lead to mental disorders are poorly understood. In this proposal we aim to investigate the hypothesis that mutation of distinct chromatin regulators converge on common gene networks to contribute to mental disorders. We suggest that mutually dependent or overlapping regulation of genetic networks essential for neuronal development and function play a role in the convergence. Mechanistically this could be mediated either by regulating hierarchical cascades of gene regulatory networks independently and/or by protein-protein interactions amongst ubiquitously expressed chromatin factors present in most cell types and neuron specific transcription factors to converge on overlapping target genes. To elucidate these possibilities, we will combine stem cell-derived induced neuronal differentiation and primary mouse neurons with functional and molecular characterization. Combining human and mouse neurons allows a controlled and detailed study of the organization of chromatin, gene regulation and neuronal activity throughout the establishment of nerve cell identity and are therefore excellent models for studying how chromatin regulators can influence neuronal function and mental illness. Specifically, we will deplete or mutate selected chromatin regulators implicated in mental disorders and study their effect on neuronal differentiation, gene expression and electrophysiological function. In addition, we will analyze the protein-protein interaction networks and epigenetic effects of these chromatin regulators to understand their molecular mechanism of action. Ultimately, our work will provide new basic insights into the gene regulatory networks involved in mental disorders and explain the potential converging role of chromatin regulators and their biochemical networks in causing these diseases.

自闭症和精神分裂症等精神障碍非常普遍，是一个巨大的健康负担。它们可以是多种多样的，具有多因素的遗传起源，但它们往往导致重叠的认知、社会和分子表型。虽然突触成分的突变可以从机制上解释患者神经元功能受损，但新出现的证据强调了几种染色质调节因子在精神障碍中的作用。然而，染色质调节因子突变导致精神障碍的潜在分子机制尚不清楚。在这个提议中，我们的目的是研究不同的染色质调节因子的突变聚集在共同的基因网络上，以促进精神障碍的假设。我们认为神经元发育和功能所必需的遗传网络相互依赖或重叠调节在趋同中发挥作用。从机制上讲，这可以通过独立调节基因调控网络的分层级联和/或通过大多数细胞类型中普遍表达的染色质因子和神经元特异性转录因子之间的蛋白质-蛋白质相互作用来介导，从而聚集在重叠的靶基因上。为了阐明这些可能性，我们将结合干细胞衍生的诱导神经元分化和小鼠原代神经元的功能和分子表征。将人类和小鼠神经元结合起来，可以在整个神经细胞身份的建立过程中对染色质的组织、基因调控和神经元活动进行控制和详细的研究，因此是研究染色质调节剂如何影响神经元功能和精神疾病的绝佳模型。具体来说，我们将耗尽或突变与精神障碍有关的染色质调节因子，并研究它们对神经元分化、基因表达和电生理功能的影响。此外，我们将分析这些染色质调节因子的蛋白-蛋白相互作用网络和表观遗传效应，以了解它们的分子作用机制。最终，我们的工作将为涉及精神障碍的基因调控网络提供新的基本见解，并解释染色质调控因子及其生化网络在导致这些疾病中的潜在聚合作用。