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

增强子RNA促进MYC-染色质相互作用调节基因表达和肿瘤发生 摘要：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 掌握生理和病理条件下基因表达的调节。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以及，如果是的话，这种相互作用将如何有助于MYC功能的了解很少。 在我们的初步研究中，我们已经证明MYC可能是一种新的RNA结合蛋白，具有 偏好与增强子RNA(ERNA)结合。除了将MYC描述为RNA结合 蛋白质，我们还发现了一个与MYC结合的Erna MERG1，它可以通过 招募MYC为其同源增强剂。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MYC的转录起重要作用 调节和致癌作用。我们提出了三个具体目标来检验我们的假设。在目标1中，我们将 研究MERG1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结合作用机制。在目标3中，我们将构建MYC-ERNA监管网络。 我们的项目将为机械研究MYC介导的基因调控增加一个新的维度。 该项目的成功完成将建立研究MYC-RNA结合功能的新工具 更广泛的MYC研究社区。MYC RNA结合功能的研究也将为MYC RNA结合功能的研究奠定基础 基金会将开发针对MYC治疗癌症的新策略。

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.