Gene regulatory network control of olfactory cortex cell type specification

嗅觉皮层细胞类型规范的基因调控网络控制

• 批准号: 10656692
• 负责人: Alexander Fleischmann
• 金额: $ 49.97万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2028-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10656692
• 关键词: ATAC-seq; Acceleration; Adult; Area; Atlases; Bayesian Analysis; Brain; Cell Lineage; Cells; Chromatin; Communities; Complement; Computational Molecular Biology; Computer Models; Coupled; Data; Data Set; Development; Differential Equation; Disease; Epigenetic Process; Gene Expression; Genetic; Goals; Health; Histologic; Knowledge; Link; Measures; Memory; Modeling; Molecular; Molecular Computers; Molecular Profiling; Motor; Mus; Neocortex; Neuronal Differentiation; Neurons; Neurosciences; Odors; Olfactory Cortex; Olfactory Pathways; Perception; Play; Positioning Attribute; Property; Publishing; Repression; Resolution; Reverse engineering; Role; Sensory; Smell Perception; Somatosensory Cortex; Specific qualifier value; System; Systems Biology; Systems Theory; Technology; Testing; Transcriptional Regulation; Work; cell type; comparative; computer science; dynamic system; experimental study; gene regulatory network; gene repression; insight; motor control; neocortical; network models; novel; olfactory bulb; piriform cortex; programs; single cell sequencing; single-cell RNA sequencing; transcription factor

Project summary Understanding brain function critically depends on knowing the identities of neural cell types. The olfactory (piriform, PCx) cortex is the main recipient of afferent inputs from the olfactory bulb and plays key roles in odor perception and memory. However, we lack a detailed molecular description of piriform cell types and the molecular machinery that defines their functional properties. Furthermore, and in contrast to sensory and motor areas in the neocortex, the genetic programs underlying PCx cell lineage specification during development remain largely unknown. A comparative analysis of cell types in the PCx and neocortex will reveal piriform- specific cell types and molecular features. Here, we propose to determine the gene expression and chromatin accessibility states of PCx neurons in the adult mouse, and to characterize the dynamic interaction of domains of regulatory chromatin and transcription factor activity that drive cell lineage specification during development. Our central hypothesis is that cell type identity in PCx is specified during development by the activity of piriform-specific gene regulatory network (GRN) activity. We further posit that GRN activity in piriform is distinct from neocortex due to the scarcity of epigenetic mechanisms for transcriptional repression. Aim 1: to identify molecularly distinct cell types in the adult olfactory cortex of mice. We will simultaneously measure gene expression and chromatin accessibility states of single cells in the mouse PCx. We predict that the molecular diversity of piriform neurons matches the diversity of their functional properties. Aim 2: to determine epigenetic mechanisms of piriform cell lineage specification during development. We will measure changes in gene expression and chromatin accessibility in developing piriform neurons and computationally reconstruct their differentiation trajectories. We predict that cell lineage specification in PCx is driven by piriform-specific dynamic interactions between domains of regulatory chromatin and associated transcription factor activity. Aim 3: to reverse engineer a gene regulatory network model for piriform cell type specification. We will infer data-driven, mechanistic GRN models for piriform and neocortex (somatosensory cortex S1) development. We will compare GRNs for PCx and neocortex using dynamical systems theory to test our model that the scarcity of repressive interactions between transcription factors drives the specification of piriform cell types. Our work will provide mechanistic insight into the epigenetic control of TF activity during neuronal differentiation and test the role of TF cross-repression in cell type specification. By integrating experimental data across PCx and neocortex, we will reveal piriform-specific cell types and the molecular features that specify the functional properties of the olfactory cortex.

项目概要 了解大脑功能关键取决于了解神经细胞类型的身份。嗅觉 （梨状，PCx）皮层是嗅球传入输入的主要接受者，在气味中起着关键作用 感知和记忆。然而，我们缺乏梨状细胞类型和梨状细胞类型的详细分子描述。 定义其功能特性的分子机械。此外，与感觉和运动相比 新皮质区域，发育过程中 PCx 细胞谱系规范的遗传程序 仍然很大程度上不为人所知。对 PCx 和新皮质中细胞类型的比较分析将揭示梨状 - 特定的细胞类型和分子特征。 在这里，我们建议确定 PCx 神经元的基因表达和染色质可及性状态 成年小鼠，并表征调节染色质和转录域的动态相互作用 在发育过程中驱动细胞谱系规范的因子活动。我们的中心假设是细胞类型 PCx 的身份在发育过程中由梨状体特异性基因调控网络 (GRN) 的活动指定 活动。我们进一步假设，由于表观遗传的缺乏，梨状核中的 GRN 活性与新皮质不同。 转录抑制机制。 目标 1：鉴定成年小鼠嗅觉皮层中分子上不同的细胞类型。我们将 同时测量小鼠 PCx 中单细胞的基因表达和染色质可及性状态。 我们预测梨状神经元的分子多样性与其功能特性的多样性相匹配。 目标 2：确定发育过程中梨状细胞谱系规范的表观遗传机制。 我们将测量梨状神经元发育过程中基因表达和染色质可及性的变化， 通过计算重建它们的分化轨迹。我们预测 PCx 中的细胞谱系规范是 由调节染色质域和相关联的梨状体特异性动态相互作用驱动 转录因子活性。目标 3：对梨状细胞的基因调控网络模型进行逆向工程 类型规范。我们将为梨状体和新皮质推断数据驱动的机械 GRN 模型 （体感皮层 S1）发育。我们将使用动态比较 PCx 和新皮质的 GRN 系统理论来测试我们的模型，即转录因子之间抑制相互作用的缺乏驱动 梨状细胞类型的规范。 我们的工作将为神经元分化过程中 TF 活性的表观遗传控制提供机制见解 并测试 TF 交叉抑制在细胞类型规范中的作用。通过整合 PCx 上的实验数据 和新皮质，我们将揭示梨状体特异性细胞类型和指定功能的分子特征 嗅觉皮层的特性。