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