MYC-bound enhancer RNAs in cis regulate gene transcription and tumorigenesis.

Abstract

Emerging evidence suggests that MYC binds RNAs, but its functional consequences remain unclear. Here, we integrate multiomics data and reveal that MYC broadly binds enhancer RNAs (eRNAs), which exhibit high cancer- and tissue-specific expression in cancer cell lines and patient tumors. Moreover, we developed a computational pipeline to identify potential cis-regulatory MYC-eRNA target genes, with most predicted eRNA-target pairs supported by RNA polymerase II-mediated chromatin interaction data. Among these, we functionally characterized <i>MERG1</i> as an oncogenic eRNA that promotes breast cancer tumorigenesis. Mechanistically, <i>MERG1</i> interacts with MYC to enhance its occupancy at the <i>GREB1</i> promoter, driving chromatin remodeling and epigenetic activation. This process specifically amplifies <i>GREB1</i> expression and promotes tumor progression. Last, nanoparticle-mediated delivery of antisense oligonucleotides targeting <i>MERG1</i> suppresses MYC-mediated breast cancer growth. These results advance our understanding of the enhancer-driven regulation of gene expression and tumorigenesis and provide insights into the regulatory landscape of MYC in cancer.