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发育和细胞身份计划的投入的集合， 致癌蛋白，代谢回路和微环境相互作用。在一起，这些最终驾驶 肿瘤启动，维持和进展的不同阶段。 desponmymoma（EPN）是一种侵略性形式 由单个遗传事件驱动的小儿脑癌，ZFTA和RELA之间的基因融合。 ZFTA-RELA （表示为Zrfus）是转化的有效驱动力，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ZRFU充当异常的转录 调节器，它用于驱动肿瘤发生的下游机制仍然很差。这个知识 差距阻碍了临床上可拖动方法的识别，而EPN一直停滞不前 超过30年。因此，该提案的总体目标是剖析Zrfus的影响和 与驱动EPN肿瘤发生的不同转录程序相交。剖析Zrfus 驱动EPN肿瘤发生后，我们在子宫内建立了Zrfus EPN的第一个自动小鼠模型 发育中的小鼠大脑的电穿孔（IUE）。使用此模型，我们证明了转录因子 （TFS）对于Zrfus EPN的启动需要发育神经发生的必不可少的（例如SOX9） 发展。在我们的模型中，这些发育TF的条形码筛选将ETV5识别为主要候选者 对于Zrfus的进展，这既是必要且足够的。在EPN中进一步检查ETV5功能 表明它通过促进抑制性染色质态抑制基因表达。在关键目标中 受ETV5抑制的基因是神经肽Y（NPY），一种有效的神经递质，我们发现了该功能至 抑制Zrfus的进展和重塑神经元边缘的神经元突触降低 活动。基于这些引人入胜的初步研究，我们假设开发编码的TFS 控制肿瘤的启动和操纵染色质的可及性，以调节肿瘤 - 神经元相互作用 在大脑微环境中，以推动EPN的生长。该假设将在以下目的中进行检验：1） 通过修改染色质可及性，确定Sox9如何影响Zrfus EPN的启动，2）破译 ETV5在Zrfus EPN进程中的作用，3）定义NPY在重塑神经元重塑中的作用 微环境。