Chromatin Regulators of MYC Oncoprotein Activity in Cancer

The MYC oncoprotein is a key contributor to the development of virtually all cancer types. MYC is known as a global regulator of transcription that controls diverse physiological and oncogenic functions. Though there are 35 yearsâ worth of research on this protein, mechanistic understanding and therapeutic targeting of MYC are still needed. We hypothesize that chromatin interactors are critical for MYC to achieve transcriptional control and biological outcomes. Our proteomic study of the MYC interactome yielded chromatin complexes and epigenetic regulators. In this thesis, we investigated two MYC-interacting complexes and defined the chromatin landscape of the MYC interactome. We characterized the novel interaction of MYC and the G9a histone methyltransferase and demonstrated their coordinated regulation of genome-wide transcriptional repression. This interaction and their resulting gene expression output support breast cancer growth, which is impaired with G9a inhibition. This study underscores the crucial role of epigenetics and epigenetic regulators in modulating MYC activity; this serves as the basis for a compelling strategy to target oncogenic MYC. We also interrogated the interaction of MYC and the SWI/SNF chromatin remodeling complex, whose many components are inactivated in a multitude of cancer types. We specifically showed the direct interaction of MYC and the INI1 subunit and their antagonistic relationship in regulating transcription and biological functions. Combining our proteomic approach with genome-wide resources, we established the chromatin landscape of the MYC interactome, defining chromatin profiles and target gene networks of known and novel MYC interactors. Collectively, these studies brought new insights to the understanding of MYC through the identification of novel chromatin interactors of MYC, their coordinated roles in regulating transcriptional activation and repression, their contributions to MYC-driven oncogenesis, and their therapeutic potential.Ph.D.2018-06-19 00:00:0