From 3D genomes to neural connectomes: Higher-order chromatin mechanisms encoding long-term memory

从 3D 基因组到神经连接组：编码长期记忆的高阶染色质机制

基本信息

批准号：
10469522
负责人：
Jennifer Elizabeth Phillips-Cremins
金额：
$ 113.75万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-15 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10469522
关键词：
3-Dimensional Address Architecture Brain CRISPR screen Cells Chromatin Data Set Defect Development Disease Engineering Epigenetic Process Exhibits Foundations Fragile X Syndrome Functional disorder Future Gene Expression Genetic Genetic Transcription Genome Genomics Goals Imaging technology In Vitro Individual Knowledge Length Light Link Maps Memory Modification Molecular Molecular Computations Neuraxis Neurodegenerative Disorders Neurodevelopmental Disorder Neurons Neurosciences Pathologic Pattern Phenotype Physiological Proteins RNA Role Somatic Cell Structure-Activity Relationship Synapses Synaptic plasticity Technology Work cell type connectome genome-wide in vivo in vivo Model insight long term memory memory consolidation memory encoding nervous system disorder neural circuit public health relevance relating to nervous system transcription factor

项目摘要

Title: From 3D genomes to neural connectomes: Higher-order chromatin mechanisms encoding long- term memory Summary The Cremins Lab focuses on higher-order genome folding and how classic epigenetic modifications work through long-range, spatial mechanisms to govern genome function in the developing brain. Much is already known regarding how transcription factors work in the context of the linear genome to regulate gene expression. Yet, severe limitations exist in our ability to engineer chromatin in neural circuits to correct synaptic defects in vivo. At the lab’s inception, it remained unclear whether and how genome folding would functionally influence cell type-specific gene expression. Thus far, we have developed and applied new molecular and computational technologies to discover that nested chromatin domains and long-range loops undergo marked reconfiguration during neural lineage commitment, somatic cell reprogramming, neuronal activity stimulation, and in repeat expansion disorders. We have demonstrated that loops induced by cortical neuron stimulation, engineered through synthetic architectural proteins, and miswired in fragile X syndrome were tightly connected to transcription, thus providing early insight into the genome’s structure-function relationship. We will now focus on a fundamental mystery in neuroscience: how memory is encoded over decades despite rapid turnover of synaptic proteins/RNAs. We hypothesize that the 3D genome integrates molecular traces of synaptic plasticity written on chromatin to store long-term memory in neural circuits. We will employ single-cell genomics and imaging technologies to dissect the extent to which individual synaptic inputs create 3D epigenetic traces. We will perform genome-wide CRISPR screens to identify specific loops and epigenetic modifications functionally important for synaptic plasticity. We will also re-direct technologies used for genome architecture mapping to create molecular activity-dependent connectome maps, and computationally integrate neuronal connectome maps across length scales with 3D epigenetic data sets. Successful completion of this work will shed new light on the genetic and epigenetic mechanisms governing structural and functional synaptic plasticity in physiologically relevant in vitro and in vivo models of memory encoding and consolidation. Many neurological disorders exhibit synaptic defects, and alterations in neuronal activity-dependent gene expression underlie pathological neural phenotypes. Addressing this knowledge gap will provide an essential foundation for our long-term goals to understand how, when, and why pathologic genome misfolding leads to synaptic dysfunction, and to engineer the 3D genome to reverse pathologic synaptic defects in debilitating neurological diseases.

标题：从3D基因组到神经连接组：编码长期的高阶染色质机制术语内存概括 Cremins Lab专注于更高的基因组折叠以及经典表观修饰的工作方式通过远程，空间机制控制发育中的大脑中的基因组功能。关于转录因子如何在线性基因组中如何起作用以调节基因表达。体内缺陷。影响细胞的类型基因表达。发现嵌套染色质域和远程环的计算技术经历了标记在神经谱系承诺，体细胞重编程，神经元活性刺激期间的重新配置，在反复扩张障碍中。通过合成的建筑蛋白进行了设计，并且在脆弱的X综合征中脱节是紧密连接的现在，我们将重点放在转录上，从而提供对基因组结构功能的早期见解。关于神经科学中的基本谜团：尽管很快流失了数十年的记忆如何编码突触蛋白/RNA。写在染色质上，以存储长期记忆在神经回路中。成像技术是为了剖析单个突触输入的程度将在功能上识别特定的循环和表观遗传修饰对于突触可塑性很重要。创建分子活性依赖性连接组图，并在计算中整合神经元连接组用3D表观遗传数据集的长度尺度上的地图。关于遗传和表观遗传机制，用于统一和功能性突触塑料许多神经与生理学相关的体外和体内记忆模型编码和整合模型疾病表现出突触缺陷和神经元活性依赖性基因expresslie中的疾病病理神经表型，解决这一知识差距将为我们的基础长期目标以了解如何，功能障碍，并在虚弱的神经病学中逆转病理突触缺陷来设计3D基因组疾病。