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.

总结 癌症中的转录网络是来自发育和细胞身份程序的输入的集合， 致癌蛋白、代谢回路和微环境相互作用。这些因素加在一起， 肿瘤起始、维持和进展的不同阶段。室管膜瘤是一种侵袭性的 一个单一的基因事件，ZFTA和RELA之间的基因融合。ZFTA-RELA （表示为ZRFUS）是转化的有力驱动因素，并且其表达足以诱导EPN， 在发育中的小鼠大脑中表达。尽管有证据表明ZRFUS作为一种异常的转录因子发挥作用， 虽然它是一种调节因子，但它用来驱动肿瘤发生的下游机制仍然不清楚。这些知识 这一差距阻碍了临床上易于处理的EPN方法的识别，这些方法在2000年以来一直停滞不前。 超过30年因此，本提案的总体目标是剖析ZRFUS如何影响和 与驱动EPN肿瘤发生的多种转录程序交叉。为了剖析ZRFUS 驱动EPN的肿瘤发生，我们建立了第一个ZRFUS EPN的子宫内原位小鼠模型， 电穿孔（IUE）的小鼠大脑发育。利用这个模型，我们证明了转录因子 (TFs)发育胶质细胞生成所必需的，如SOX 9，是启动ZRFUS EPN所必需的 发展在我们的模型中，这些发育TF的条形码筛选将ETV 5确定为主要候选者 这对于ZRFUS进展来说是必要的和充分的。EPN中ETV 5功能的进一步检查 揭示了它通过促进抑制性染色质状态来抑制基因表达。在关键目标中， 被ETV 5抑制的基因是神经肽Y（NPY），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， 活动基于这些令人信服的初步研究，我们假设发育编码的TF 控制肿瘤的发生和操纵染色质的可接近性，从而调节肿瘤-神经元的相互作用 来驱动EPN的生长这一假设将在以下目标中得到检验：1） 确定SOX 9如何通过改变染色质可及性影响ZRFUS EPN起始，2）破译 ETV 5在ZRFUS EPN进展中的作用，以及3）确定NPY在室管膜瘤神经元重塑中的作用 微环境