Cell-state specific 3D genome architecture in heterogeneous cell populations of the brain.

大脑异质细胞群中细胞状态特定的 3D 基因组结构。

• 批准号: 422857012
• 负责人: Professorin Dr. Ana Pombo, Ph.D.
• 金额: --
• 依托单位: Max-Delbrück-Centrum für Molekulare Medizin (MDC) in der Helmholtz-Gemeinschaft
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/422857012?language=en
• 关键词: Cell; state; specific; 3D; genome

Accurate levels of gene expression during development and in environmental responses are mediated through specific three-dimensional (3D) contacts between non-coding regulatory regions and their target genes. Defects in the spatial relationship of regulatory elements to their target genes are linked to disease, and are increasingly important to understand complex neurological disorders, often associated with deregulation of chromatin factors. However, efforts to study 4D genome architecture in the nervous system have been limited to the use of bulk tissues, cells differentiated in vitro or neurons dissociated from the brain. Thus, it remains a major challenge to dissect the 4D nucleome alterations that accompany activation processes in specific neurons, and how they relate with homeostatic responses during neuronal activation and in circadian processes. In this proposal, we aim to understand the relationship between the 4D genome and gene expression in specific cells of the brain, and its deregulation in neurodevelopmental disorders associated with Shank3 mutations, which are risk factors for Autism Spectrum Disorders (ASD). Further to its synaptic roles, Shank3 shuttles to the nucleus where it modulates gene expression in response to neuronal activity. First, we will determine 3D genome topologies in specialized pyramidal neurons in the hippocampus of wildtype and mutant Shank3 mice, to investigate Shank3 genomic targets and mechanisms of action. Second, we will develop a novel technology to dissect quantitative relationships between 3D folding patterns and cellular levels of nuclear factors, an essential step towards finer dissection of 3D genome folding mechanisms in heterogeneous tissues such as the brain.

在发育过程中和环境响应中基因表达的准确水平是通过非编码调控区与其靶基因之间的特异性三维（3D）接触介导的。调控元件与其靶基因的空间关系的缺陷与疾病有关，并且对于理解复杂的神经系统疾病越来越重要，通常与染色质因子的失调有关。然而，在神经系统中研究4D基因组结构的努力仅限于使用大块组织、体外分化的细胞或从大脑分离的神经元。因此，它仍然是一个主要的挑战，解剖4D核组的变化，伴随着特定神经元的激活过程，以及它们如何与神经元激活和昼夜节律过程中的稳态反应。在这项提案中，我们的目标是了解4D基因组与大脑特定细胞中基因表达之间的关系，以及与Shank3突变相关的神经发育障碍中的失调，这是自闭症谱系障碍（ASD）的危险因素。除了其突触作用外，Shank3穿梭于细胞核，在那里它调节基因表达以响应神经元活动。首先，我们将确定野生型和突变型Shank3小鼠海马中专门锥体神经元的3D基因组拓扑结构，以研究Shank3基因组靶点和作用机制。其次，我们将开发一种新的技术来解剖3D折叠模式和细胞水平的核因子之间的定量关系，这是朝着更精细地解剖异质组织（如大脑）中的3D基因组折叠机制迈出的重要一步。