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.

项目摘要 了解大脑功能关键取决于知道神经细胞类型的身份。嗅 （梨状，PCx）皮层是嗅球传入信息的主要接受者，在嗅觉中起着关键作用 感知和记忆然而，我们缺乏梨状细胞类型的详细分子描述， 决定其功能特性的分子机制。此外，与感觉和运动相反， 在新皮层的区域，在发育过程中PCx细胞谱系特化的遗传程序 但基本上仍不为人所知。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，并表征调控染色质和转录结构域的动态相互作用 在发育过程中驱动细胞谱系特化的因子活性。我们的核心假设是细胞类型 PCx的同一性在发育过程中由梨状核特异性基因调控网络（GRN）的活性决定 活动我们进一步证实，GRN活动在梨状核是不同的新皮质，由于缺乏表观遗传 转录抑制机制。 目的1：鉴定成年小鼠嗅皮质中不同的细胞类型。我们将 同时测量小鼠PCx中单个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。 目的2：确定发育过程中梨状细胞谱系特化的表观遗传机制。 我们将测量发育中梨状神经元的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中的细胞谱系特化是 由调节染色质结构域和相关的梨状核特异性动态相互作用驱动 转录因子活性。目的3：建立梨状细胞基因调控网络模型 类型说明我们将推断梨状核和新皮层的数据驱动的，机械的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性相互作用的缺乏驱动了 梨状细胞类型的特化。 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上的见解 并检测TF交叉阻遏在细胞类型特化中的作用。通过整合PCx中的实验数据 和新皮层，我们将揭示梨状核特异性细胞类型和指定功能的分子特征， 嗅觉皮层的特性。