High-throughput Discovery of Novel Genome Organization Regulators

新型基因组组织调节因子的高通量发现

• 批准号: 10777403
• 负责人: Bo Xia
• 金额: $ 29.27万
• 依托单位: BROAD INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-20 至 2024-09-19
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10777403
• 关键词: 3-Dimensional; Address; Affect; Algorithms; Binding; Binding Proteins; Binding Sites; Boundary Elements; CCCTC-binding factor; Candidate Disease Gene; Categories; Cell Line; Chromatin; Chromatin Loop; Clustered Regularly Interspaced Short Palindromic Repeats; Complex; Consumption; DNA; Disease; Elements; Enhancers; Frequencies; Funding; Future; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genetic Screening; Genome; Hi-C; Human; Human BioMolecular Atlas Program; Interphase; Interphase Chromosome; Investigation; Knock-out; Knowledge; Measures; Mediating; Nature; Network-based; Neural Network Simulation; Pilot Projects; Process; Regulation; Regulatory Element; Reporter; Resolution; Resources; Standardization; Structure; System; T-Lymphocyte; Technology; United States National Institutes of Health; Validation; Work; YY1 Transcription Factor; acute T-cell lymphoblastic leukemia cell; cell type; chromosome conformation capture; cohesin; deep neural network; denoising; design; epigenomics; experimental study; follow-up; genomic data; in silico; multimodality; novel; programs; promoter; reverse genetics; scale up; screening

ABSTRACT CTCF binding at its convergent-orientated DNA motifs has been implicated in establishing TAD boundary. CTCF protein regulates the genome organization through cohesin complex-mediated loop extrusion mechanism. While a few more factors have been recently discovered to regulate genome organization, such as NIPBL, WAPL, YY1, ZNF143, and MAZ, it is still far from a comprehensive mechanistic understanding of how the genome is organized. Discovering novel regulators of genome organization is still challenging due to the intensive nature of chromatin conformation capture technologies. To address the technical challenge in measuring genome organization, we have recently demonstrated that a deep neural network approach can enable de novo prediction of cell type- specific chromatin organization at high resolution. Moreover, this deep neural network model enables high- throughput in silico genetic screen (ISGS) for identifying cell type-specific DNA elements that are important for chromatin interactions. To fully unlock the discovery potential of this deep neural network-based ISGS approach, here we propose to leverage the NIH Common Fund-supported large-scale genomic data across human bio- samples for discovering novel regulators in 3D genome organization. We will predict a list of high-confidence trans-acting regulators, and experimentally validate 3-5 top hits in pilot studies to generate cross-cutting hypotheses for future research in 3D genome regulation.

抽象的 CTCF 与其聚合导向 DNA 基序的结合与 TAD 边界的建立有关。 CTCF 蛋白质通过粘连蛋白复合物介导的环挤出机制调节基因组组织。尽管 最近还发现了一些调节基因组组织的因子，例如 NIPBL、WAPL、YY1、 ZNF143和MAZ，距离对基因组如何组织的全面机制理解还很远。 由于染色质的密集性质，发现基因组组织的新型调节因子仍然具有挑战性 构象捕获技术。为了解决测量基因组组织的技术挑战，我们 最近证明深度神经网络方法可以实现细胞类型的从头预测 高分辨率的特定染色质组织。此外，这种深度神经网络模型能够实现高 计算机模拟遗传筛选 (ISGS) 的通量，用于识别对细胞类型重要的特定细胞类型 DNA 元件 染色质相互作用。为了充分释放这种基于深度神经网络的 ISGS 方法的发现潜力， 在这里，我们建议利用 NIH 共同基金支持的跨人类生物的大规模基因组数据 用于发现 3D 基因组组织中新型调节因子的样本。我们将预测一份高置信度名单 反式作用调节剂，并通过实验验证试点研究中的 3-5 个热门命中，以产生跨领域 3D 基因组调控未来研究的假设。