Transcriptional Regulation in ZFTA-RELA Ependymoma

ZFTA-RELA 室管膜瘤的转录调控

• 批准号: 10736436
• 负责人: Benjamin Deneen
• 金额: $ 66.35万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10736436
• 关键词: Bar Codes; Brain; Brain Neoplasms; Cell Proliferation; Cells; Childhood Malignant Brain Tumor; Chromatin; Chromatin Remodeling Factor; Clinical; Collection; Coupled; Data; Development; Disparate; Electroencephalography; Electroporation; Embryo; Ependymoma; Epigenetic Process; Event; Gene Expression; Gene Expression Profile; Gene Expression Regulation; Gene Fusion; Genetic; Genetic Transcription; Genome; Goals; Growth; Histones; Human; Hyperactivity; Knowledge; Lead; Maintenance; Malignant Neoplasms; Malignant neoplasm of brain; Mediator; Metabolic; Modeling; Mus; Neuroglia; Neurons; Neuropeptides; Neurotransmitters; Oncogenic; Pathway interactions; Patients; Proteins; RELA gene; Radial; Regulation; Repression; Role; SMARCA4 gene; Seizures; Shapes; Site; Synapses; Testing; Tissue-Specific Gene Expression; Transcriptional Regulation; Tumor stage; epigenomics; gene repression; gliogenesis; human model; in utero; lead candidate; loss of function; member; mouse model; neuronal tumor; neuropeptide Y; novel; overexpression; programs; protein protein interaction; screening; transcription factor; tumor; tumor initiation; tumor progression; tumorigenesis

SUMMARY Transcriptional networks in cancer are a collection of inputs from developmental and cell identity programs, oncogenic proteins, metabolic circuits, and micro-environmental interactions. Together, these culminate to drive disparate stages of tumor initiation, maintenance, and progression. Ependymoma (EPN) is an aggressive form of pediatric brain cancer driven by a single genetic event, a gene fusion between ZFTA and RELA. ZFTA-RELA (denoted ZRFUS) is a potent driver of transformation, and its expression is sufficient to induce EPN when expressed in the developing mouse brain. Despite evidence that ZRFUS functions as an aberrant transcriptional regulator, the downstream mechanisms it utilizes to drive tumorigenesis remain poorly defined. This knowledge gap has hindered the identification of clinically tractable approaches for EPN, which have remained stagnant for over 30 years. Therefore the overarching goal of this proposal is to dissect how ZRFUS impacts and intersects with the diverse transcriptional programs that drive EPN tumorigenesis. To dissect how ZRFUS drives EPN tumorigenesis, we established the first autochthonous mouse model of ZRFUS EPN using in utero electroporation (IUE) of the developing mouse brain. Using this model, we demonstrated that transcription factor (TFs) essential for developmental gliogenesis, such as SOX9, are required for the initiation of ZRFUS EPN development. Barcode screening of these developmental TFs in our model identified ETV5 as a lead candidate that is both necessary and sufficient for ZRFUS progression. Further examination of ETV5 function in EPN revealed that it suppresses gene expression by promoting repressive chromatin states. Among the key target genes repressed by ETV5 is Neuropeptide Y (NPY), a potent neurotransmitter, which we found functions to suppress ZRFUS progression and remodel neuronal synapses in the peritumoral margins towards decreased activity. Based on these compelling preliminary studies, we hypothesize that developmentally encoded TFs govern tumor initiation and manipulate chromatin accessibility that regulate tumor-neuron interactions in the brain microenvironment to drive EPN growth. This hypothesis will be tested in the following aims: 1) Determine how SOX9 impacts ZRFUS EPN initiation through modifying chromatin accessibility, 2) Decipher the role of ETV5 in ZRFUS EPN progression, and 3) Define the role of NPY in remodeling the ependymoma neuronal microenvironment.

概括 癌症中的转录网络是来自发育和细胞识别程序的输入的集合， 致癌蛋白、代谢回路和微环境相互作用。这些共同推动了 肿瘤发生、维持和进展的不同阶段。室管膜瘤 (EPN) 是一种侵袭性形式 由单一遗传事件（ZFTA 和 RELA 之间的基因融合）驱动的小儿脑癌。 ZFTA-RELA （表示为 ZRFUS）是转化的有效驱动因素，其表达足以诱导 EPN 在发育中的小鼠大脑中表达。尽管有证据表明 ZRFUS 具有异常转录功能 尽管它是调节剂，但其用于驱动肿瘤发生的下游机制仍不清楚。这些知识 差距阻碍了临床上可处理的 EPN 方法的识别，这些方法多年来一直停滞不前 超过30年。因此，该提案的首要目标是剖析 ZRFUS 如何影响和 与驱动 EPN 肿瘤发生的多种转录程序相交叉。剖析 ZRFUS 如何 驱动 EPN 肿瘤发生，我们建立了第一个在子宫内使用的 ZRFUS EPN 小鼠模型 发育中的小鼠大脑的电穿孔（IUE）。使用这个模型，我们证明了转录因子 ZRFUS EPN 的启动需要发育胶质细胞生成所必需的 (TF)，例如 SOX9 发展。在我们的模型中对这些发育转录因子进行条形码筛选，确定 ETV5 为主要候选者 这对于 ZRFUS 进展来说既是必要的也是充分的。进一步检验 ETV5 在 EPN 中的功能 研究表明，它通过促进抑制染色质状态来抑制基因表达。其中重点目标 ETV5 抑制的基因是神经肽 Y (NPY)，它是一种有效的神经递质，我们发现它的功能是 抑制 ZRFUS 进展并重塑肿瘤周围边缘的神经元突触以减少 活动。基于这些令人信服的初步研究，我们假设发育编码的转录因子 控制肿瘤的发生并操纵染色质的可及性，从而调节肿瘤-神经元的相互作用 在大脑微环境中驱动 EPN 生长。该假设将在以下目标中进行检验：1） 确定 SOX9 如何通过修改染色质可及性来影响 ZRFUS EPN 启动，2) 破译 ETV5 在 ZRFUS EPN 进展中的作用，以及 3) 定义 NPY 在室管膜瘤神经元重塑中的作用 微环境。