Deciphering the 3D genome of pediatric brain tumors

破译儿童脑肿瘤的 3D 基因组

• 批准号: 10585741
• 负责人: Nadia Dahmane
• 金额: $ 39.12万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-20 至 2024-09-19
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10585741
• 关键词: 3-Dimensional; Abnormal Cell; Affect; Age-Months; Architecture; Biology; Brain; Brain Neoplasms; Cell Differentiation process; Cell Line; Cells; Cerebellum; Child; Childhood; Childhood Brain Neoplasm; Childhood Malignant Brain Tumor; Chromatin; Code; Computing Methodologies; DNA Sequence; Data; Data Set; Defect; Development; Developmental Process; Disease; Embryonic Development; Ependymoma; Epigenetic Process; Etiology; Event; Frequencies; Funding; Future; Gene Expression; Gene Expression Regulation; Genetic; Genome; Genomics; Genotype; Glioma; Institutes; Lead; Link; Malignant - descriptor; Malignant Childhood Neoplasm; Malignant Neoplasms; Maps; Medicine; Modeling; Morbidity - disease rate; Neurologic Effect; Normal tissue morphology; Output; Pathogenesis; Patients; Pediatric Hospitals; Pediatric Neoplasm; Philadelphia; Pilot Projects; Play; Proteins; Publishing; Recurrence; Refractory; Research; Rhabdoid Tumor; Role; SHH gene; SMARCA4 gene; SMARCB1 gene; Sampling; Single Nucleotide Polymorphism; Solid Neoplasm; Testing; Therapeutic; Tissues; Training; Untranslated RNA; Variant; aggressive therapy; bioinformatics pipeline; cohort; data integration; deep learning; deep learning model; experimental study; genetic variant; innovation; insertion/deletion mutation; interest; medulloblastoma; multidisciplinary; nerve stem cell; new therapeutic target; novel; postnatal development; programs; promoter; prototype; single-cell RNA sequencing; smoothened signaling pathway; stem cells; tool; transcriptome; tumor; tumorigenesis; whole genome

Project Summary Pediatric brain tumors are the most frequent cause of morbidity in children with solid tumors. Importantly, the aggressive therapeutic regiments often lead to debilitating neurological effects. The realization that developmental processes critical to brain development are also deregulated in cancer has provided new hope for understanding and treating brain tumors. Indeed, single cell-RNAseq analyses have further demonstrated the role of defects in lineage determination for pediatric brain tumors. To discover novel drivers of tumorigenesis, we will focus on the function of three-dimensional (3D) genome folding in pediatric brain tumors. Indeed, 3D chromatin interactions are involved in gene expression regulation, and changes in genome folding are linked to cell identity acquisition during development. While there is increasing interest in elucidating the function of 3D genome architecture during developmental processes and in cancer, how the 3D genome is organized in different pediatric brain tumors and its roles in tumor formation and progression are unknown. We hypothesize that disrupted 3D genome folding during embryonic or postnatal development alters gene expression leading to abnormal cell differentiation and tumorigenesis in the developing brain. To test our hypothesis, we will comprehensively interrogate the genomes of pediatric brain tumors for non-coding variants that may affect 3D genome folding. We will use a deep-learning model called Akita that predicts 3D chromatin interaction frequencies from genome sequence alone. Because Akita only requires DNA sequence as input, we can predict the effect of any variant within a single framework that accommodates single-nucleotide variants (SNVs), insertion/deletions (indels), and structural variation (SVs). Akita will be used with pediatric brain whole genome sequences (WGS) from Gabriella Miller Kids First (KF) plus chromatin capture, epigenetic, and expression data from the 4D Nucleome (4DN) and Genotype-Tissue Expression (GTEx) programs in the following aims: 1) Determine the 3D genome architecture of Atypical teratoid/rhabdoid tumor AT/RT tumors. We have initiated our study using AT/RT, tumors thought to be due to defects in early development11 and the most common brain tumor in children less than six months of age. 1.A. We will develop a bioinformatics pipeline that uses Akita to quantify how much a genetic variant is predicted to disrupt 3D chromatin interactions in AT/RT tumors. 1.B. We will validate and determine the functional relevance of 3D genomic folding disruptions observed in AT/RT tumors. 2) Determine the 3D genome architecture of malignant pediatric tumors. We will extend our analyses with Akita to additional malignant pediatric brain tumors, focusing for this pilot project on the most malignant and treatment refractory tumors. This innovative project, using a new deep-learning tool Akita, will lead to, novel research hypotheses and will accelerate the discovery of additional regulators of pediatric cancer tumorigenesis and thus to potential therapeutic strategies for these devastating diseases.

项目摘要 儿童脑肿瘤是儿童实体瘤发病的最常见原因。重要的是 积极的治疗方案经常导致使人衰弱的神经作用。意识到 对大脑发育至关重要的发育过程在癌症中也被解除管制， 来了解和治疗脑肿瘤。事实上，单细胞RNAseq分析进一步证明了 缺陷在儿科脑肿瘤谱系确定中的作用。为了发现肿瘤发生的新驱动因素， 我们将集中在儿童脑肿瘤的三维（3D）基因组折叠的功能。事实上，3D 染色质相互作用参与基因表达调控，基因组折叠的变化与 在开发过程中获取细胞身份。虽然人们越来越关注阐明3D的功能， 在发育过程中的基因组结构和癌症中，3D基因组是如何组织的， 不同的小儿脑肿瘤及其在肿瘤形成和发展中的作用尚不清楚。我们假设 在胚胎或出生后发育过程中破坏3D基因组折叠，改变基因表达， 发育中的大脑中的异常细胞分化和肿瘤发生。为了验证我们的假设，我们将 全面询问儿科脑肿瘤的基因组，以寻找可能影响3D的非编码变体。 基因组折叠我们将使用一种名为秋田的深度学习模型，该模型预测3D染色质相互作用 基因组序列的频率。因为秋田只需要DNA序列作为输入，我们可以预测 在容纳单核苷酸变体（SNV）的单个框架内的任何变体的作用， 插入/缺失（indels）和结构变异（SV）。秋田将用于儿科脑全基因组 来自Gabriella米勒儿童优先（KF）的WGS序列加上染色质捕获、表观遗传和表达数据 来自4D核组（4DN）和基因型-组织表达（GTEx）计划，目的如下：1） 确定非典型畸胎样/横纹肌样肿瘤AT/RT肿瘤的3D基因组结构。我们已经启动了我们的 使用AT/RT的研究，肿瘤被认为是由于早期发育缺陷11和最常见的大脑 肿瘤发生在6个月以下的儿童身上。1.a.我们将开发一个生物信息学管道，使用秋田， 量化预测遗传变异破坏AT/RT肿瘤中3D染色质相互作用的程度。1.b.我们 将验证和确定在AT/RT肿瘤中观察到的3D基因组折叠破坏的功能相关性。 2)确定儿科恶性肿瘤的3D基因组结构。我们将对秋田进行分析 其他恶性儿科脑肿瘤，重点是这个试点项目的最恶性和治疗 难治性肿瘤这一创新项目使用了一种新的深度学习工具秋田，将导致新的研究 假设，并将加速发现儿科癌症肿瘤发生的其他调节因子， 这些毁灭性疾病的潜在治疗策略。