Mechanisms of transcriptional regulation by oncogenic MYC

Cancer is a heterogeneous disease, with each type and subtype having a unique molecular basis. One common factor identified to promote oncogenic activities in up to 70% of all cancers is MYC. The oncoprotein MYC is a master transcription factor regulating gene expression of many genes driving cancer development. Although MYC was discovered more than 40 years ago, its cancer-specific transcriptional roles remain elusive. Recently, the ability of MYC to bind promoter distal regions has been acknowledged, however, the transcriptional role of MYC at these cis-regulatory regions is still poorly understood. Therefore, a better understanding of the transcriptional mechanism of MYC at gene distal regions is pivotal for our understanding of the mechanisms driving cancer development.

The overarching goal of this Ph.D. was to obtain mechanistic insight into the transcriptional role of MYC at promoter distal enhancer regions and how this function of MYC is involved in the regulation of genes important for cancer development. We profiled genome-wide changes in chromatin accessibility, transcription factor/coregulator binding, and gene expression across different breast cancer cell lines, in combination with perturbation of MYC function. This allowed us to investigate the transcriptional function of MYC globally. In the main work of this Ph.D. project presented in Appendix 1, we show that MYC invades, cancer-specific enhancers together with cancer-specific transcription factors to regulate genes with prognostic value. We discover that MYC is important for enhancer activity and transcription, surprisingly this mechanism is through RNA polymerase II recruitment rather than regulation of RNA polymerase II pause/release, as is the case at gene promoters. This mechanism likely depends on the combined actions of GCN5 and KDM3A leading to an epigenetic switch at histone 3 lysine 9. These discoveries were highly relevant as MYC enhancer invasion previously has been described to be spillover without any transcriptional function. Altogether, we suggest a mechanism where MYC drive prognostics cancer-specific genes through recruitment of RNA polymerase II to enhancers, potential through a GCN5-KDMA3A mediated epigenomic switch.