Enhancer RNAs Boost MYC-Chromatin Interaction to Regulate Gene Expression and Tumorigenesis

增强子 RNA 促进 MYC-染色质相互作用以调节基因表达和肿瘤发生

• 批准号: 10716358
• 负责人: Da Yang
• 金额: $ 43.4万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10716358
• 关键词: Binding; Biological Assay; Bromodomains and extra-terminal domain inhibitor; ChIP-seq; Chromatin; Chromatin Interaction Analysis by Paired-End Tag Sequencing; Clustered Regularly Interspaced Short Palindromic Repeats; Communities; DNA; DNA Binding; Data; Dimensions; Dimerization; EMSA; Enhancers; Estrogen Receptor alpha; Estrogen receptor positive; Foundations; GREB1 gene; Gene Amplification; Gene Expression; Gene Expression Regulation; Goals; Growth; In Vitro; Invaded; Investigation; MYC Family Protein; Malignant Neoplasms; Mammary Gland Parenchyma; Mediating; Molecular; Oncogenes; Oncogenic; Pathologic; Physiological; Play; RNA; RNA Binding; RNA-Binding Proteins; Regulation; Regulator Genes; Reporter; Research; Role; Small Interfering RNA; Technology; Testing; Transcriptional Regulation; design; in vivo; knock-down; malignant breast neoplasm; novel; novel strategies; overexpression; preference; promoter; recruit; tool; transcription factor; tumor; tumor growth; tumorigenesis

Enhancer RNAs Boost MYC-Chromatin Interaction to Regulate Gene Expression and Tumorigenesis Summary: Our long-term goal is to determine how MYC’s RNA binding function contributes to its role as a master regulator of gene expression in physiological and pathological conditions. In last three decades, MYC has been extensively studied as a DNA-binding transcription factor. However, whether MYC can interact with RNA and, if yes, how such interactions would contribute to MYC function are poorly understood. In our preliminary study, we have shown that MYC may be a novel RNA-binding protein with a preference to bind with enhancer RNAs (eRNAs). In addition to characterizing MYC as an RNA-binding protein, we have also identified a MYC-bound eRNA MERG1 that can regulate breast cancer growth via recruiting MYC to its cognate enhancer. With these observations, we hypothesize that (1) MYC is an RNA- binding protein and (2) eRNA-mediated MYC-chromatin binding is important for MYC’s transcriptional regulation and oncogenic function. We propose three specific aims to test our hypotheses. In Aim 1, we will investigate if MERG1 is an oncogenic eRNA in ER+ breast cancer. In aim 2, we will investigate the molecular mechanism of MYC’s RNA binding function. In aim 3, we will build MYC-eRNA regulatory network. Our project will add a new dimension to mechanistically study the MYC-mediated gene regulation. Successful completion of the project will establish novel tools to investigate MYC-RNA binding function for the broader MYC research community. The investigation of MYC RNA binding function will also lay the foundation to develop novel strategy to target MYC in cancer.

增强子RNA增强MYC-染色质相互作用以调节基因表达和肿瘤发生 总结：我们的长期目标是确定MYC的RNA结合功能如何有助于其作为一种免疫调节剂的作用。 生理和病理条件下基因表达的主要调节因子。在过去的三十年里，MYC 作为一种DNA结合转录因子已被广泛研究。然而，MYC是否可以与 RNA，如果是的话，这种相互作用如何有助于MYC功能还知之甚少。 在我们的初步研究中，我们已经表明MYC可能是一种新的RNA结合蛋白， 优先与增强子RNA（eRNA）结合。除了将MYC表征为RNA结合蛋白之外， 蛋白，我们还确定了MYC结合的eRNAMERG 1，可以通过调节乳腺癌的生长， 将MYC募集到其同源增强子中。根据这些观察，我们假设（1）MYC是一种RNA- 结合蛋白和（2）eRNA介导的MYC-染色质结合对于MYC的转录是重要的 调节和致癌功能。我们提出了三个具体目标来验证我们的假设。在目标1中，我们 研究MERG 1是否是ER+乳腺癌中的致癌eRNA。在目标2中，我们将研究分子 MYC的RNA结合功能。目标3：构建MYC-eRNA调控网络。 我们的项目将为MYC介导的基因调控机制的研究增加一个新的维度。 该项目的成功完成将建立新的工具来研究MYC-RNA结合功能， 更广泛的MYC研究社区。对MYC RNA结合功能的研究也将为MYC的研究奠定基础。 基金会开发新的战略，以靶向癌症中的MYC。