ChIP-Seq of MYC in MCF-7 cells treated with AM (Actinomycin D and MG132) or DMSO.

MYC has been known to bind to thousands of promoters and exert an amplification effect on expression of most genes. Meanwhile, MYC drives tumorigenesis through the regulation of a unique set of cancer-specific targets that differ from its targets in normal cells. However, the mechanism underlying this discrepancy in MYC’s regulation in tumor and normal cells has not been fully elucidated. In this study, we discovered that MYC protein has a broad RNA binding spectrum including promoter-associated RNAs (paRNAs) and enhancer RNAs (eRNAs). MYC’s RNA binding peaks colocalize with its DNA binding sites, but not dependent on its HLHLZ domain or transcription activation domain. By further integrating multiple dimensional data from cancer cells and tumors samples, we have shown that the MYC-bound paRNAs and eRNAs can shape MYC chromatin interaction to regulate gene transcription. Finally, we have mechanistically characterized a MYC-bound eRNA, MERG1, that plays essential roles in the ERα+ breast cancer tumorigenesis. Mechanistically, MERG1 interacts with MYC and enhances MYC’s binding to the enhancer and promoter of GREB1 gene. This process specifically amplifies the target gene GREB1 expression and accelerates tumor progression. Our study demonstrates that MYC’s interaction with paRNAs and eRNAs contribute to its specific amplification of gene expression in tumorigenesis.