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

• 批准号: 10674017
• 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
• 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/10674017
• 关键词: 3-Dimensional; Address; Architecture; Brain; CRISPR screen; Cell Reprogramming; Cells; Central Nervous System; 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; Link; Maps; Memory; Modification; Molecular; Neurodegenerative Disorders; Neurodevelopmental Disorder; Neurons; Neurosciences; Pathologic; Pattern; Phenotype; Physiological; Proteins; RNA; Role; Somatic Cell; Structure-Activity Relationship; Synapses; Synaptic plasticity; Technology; Work; Writing; cell type; connectome; genome-wide; in vivo; in vivo Model; insight; long term memory; memory consolidation; memory encoding; nervous system disorder; neural; neural circuit; public health relevance; transcription factor

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专注于高阶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。已经很多了 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。然而，我们在神经回路中设计染色质以纠正突触的能力存在严重限制 体内缺陷。在实验室的成立时，仍不清楚基因组是否以及如何在功能上折叠 影响细胞类型特异性基因表达。那远，我们已经开发和应用了新的分子， 计算技术发现嵌套的染色质域和远程循环经历了标记 在神经林的承诺，体细胞重编程，神经元活性刺激期间的重新配置， 并重复扩张障碍。我们已经证明了由皮质神经元刺激诱导的环， 通过合成的建筑蛋白设计，易碎X综合征的Wired紧密连接 转录，从而提供了对基因组结构功能关系的尽早见解。我们现在将集中精力 关于神经科学的基本谜团：数十年来如何编码记忆 突触蛋白/RNA。我们假设3D基因组整合突触可塑性的分子痕迹 写在染色质上，以将长期记忆存储在神经回路中。我们将采用单细胞基因组学和 成像技术剖析单个突触输入产生3D表观遗传痕迹的程度。我们 将执行全基因组CRISPR屏幕，以识别特定的回路和表观遗传修饰功能 对于突触可塑性很重要。我们还将重新指导用于基因组架构映射的技术 创建分子活性依赖性连接组图，并计算整合的神经元连接组 带有3D表观遗传数据集的长度尺度的地图。成功完成这项工作将使新的光芒 关于管理结构和功能突触可塑性的遗传和表观遗传机制 体外和体内记忆编码和巩固的体内模型。许多神经系统 疾病暴露的合成缺陷和神经元活性依赖性基因表达的改变是基础 病理神经表型。解决这一知识差距将为我们的基础提供基础 长期目标，以了解如何，何时以及为什么病理基因组错误折叠会导致突触 功能障碍，并设计3D基因组以使神经系统衰弱的病理突触缺陷 疾病。

项目成果

3D genome, on repeat: Higher-order folding principles of the heterochromatinized repetitive genome.

• DOI: 10.1016/j.cell.2022.06.052
• 发表时间: 2022-07-21
• 期刊: CELL
• 影响因子: 64.5
• 作者: Haws, Spencer A.;Simandi, Zoltan;Barnett, R. Jordan;Phillips-Cremins, Jennifer E.
• 通讯作者: Phillips-Cremins, Jennifer E.

A multi-looping chromatin signature predicts dysregulated gene expression in neurons with familial Alzheimer's disease mutations.

多环染色质特征可预测患有家族性阿尔茨海默病突变的神经元中基因表达失调。

• DOI: 10.1101/2024.02.27.582395
• 发表时间: 2024
• 期刊: bioRxiv : the preprint server for biology
• 作者: Chandrashekar,Harshini;Simandi,Zoltan;Choi,Heesun;Ryu,Han-Seul;Waldman,AbrahamJ;Nikish,Alexandria;Muppidi,SrikarS;Gong,Wanfeng;Paquet,Dominik;Phillips-Cremins,JenniferE
• 通讯作者: Phillips-Cremins,JenniferE

Cohesin-dependence of neuronal gene expression relates to chromatin loop length.

• DOI: 10.7554/elife.76539
• 发表时间: 2022-04-26
• 期刊: eLife
• 影响因子: 7.7
• 作者: Calderon L;Weiss FD;Beagan JA;Oliveira MS;Georgieva R;Wang YF;Carroll TS;Dharmalingam G;Gong W;Tossell K;de Paola V;Whilding C;Ungless MA;Fisher AG;Phillips-Cremins JE;Merkenschlager M
• 通讯作者: Merkenschlager M