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

基本信息

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
项目类别：
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

项目摘要

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 促进 MYC-染色质相互作用以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 结合功能如何发挥其作为在过去的三十年里，MYC 是生理和病理条件下基因表达的主要调节者。然而，MYC 是否可以与 DNA 结合转录因子相互作用。人们对 RNA 以及这种相互作用如何促进 MYC 功能知之甚少。在我们的初步研究中，我们已经证明 MYC 可能是一种新型 RNA 结合蛋白，具有除了将 MYC 描述为 RNA 结合剂外，还偏好与增强子 RNA (eRNA) 结合。蛋白质，我们还发现了一种结合 MYC 的 eRNA MERG1，它可以通过调节乳腺癌的生长将 MYC 募集到其同源增强子中通过这些观察，我们认为 (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 的转录非常重要我们提出三个具体目标来检验我们的假设。研究 MERG1 是否是 ER+ 乳腺癌中的致癌 eRNA 在目标 2 中，我们将研究该分子。 MYC的RNA结合功能机制在目标3中，我们将构建MYC-eRNA调控网络。我们的项目将为机械地研究 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新的工具来研究 MYC-RNA 结合功能更广泛的 MYC 研究界对 MYC RNA 结合功能的研究也将奠定基础。基金会开发针对癌症 MYC 的新策略。