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.

摘要 CTCF结合在其收敛方向的DNA基序已牵连在建立的DNA边界。CTCF 蛋白通过粘附素复合物介导的环挤出机制调节基因组的组织。而 最近又发现了一些调节基因组结构的因子，如NIPBL，WAPL，YY 1， ZNF 143和MAZ，它仍然远远没有一个全面的机制理解基因组是如何组织的。 由于染色质的密集性，发现新的基因组组织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 最近已经证明，深度神经网络方法可以实现细胞类型的从头预测- 高分辨率的特异性染色质组织。此外，这种深度神经网络模型可以实现高- 用于鉴定细胞类型特异性DNA元件的计算机遗传筛选（ISGS），所述细胞类型特异性DNA元件对于 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， 在3D基因组组织中发现新的调节器的样本。我们将预测一份高置信度的 反式作用调节器，并在试点研究中通过实验验证3-5个最佳结果，以产生交叉 3D基因组调控未来研究的假设。