Super-Enhancers Orchestrate Transcriptional Dysregulation and Metabolic Reprogramming in Uveal Melanoma

Abstract

Abstract Uveal melanoma (UM) is the most common intraocular malignancy which frequently metastasizes. Somatic mutations and chromatin aberrations have been identified in the pathogenesis of this deadly disease. Despite rapid progress in uveal melanoma genetic landscape, the epigenetic architecture in UM pathogenesis has not been fully clarified. Here, we describe a super enhancer-medicated epigenetic pipeline via genome-scale histone acetylation modification as well as transcriptional profiling. We first characterize an active landscape of super enhancer profiles in UM with ChIP-seq. We identify master transcription factors specifically driven by UM-specific super enhancers, and our pipeline unveils the transcription factor TFAP2A as the top essential regulator in UM, which is highly associated with metabolism and oncogenesis. TFAP2A occupies predicted super enhancers associated with the oncogene SLC7A8 in UM, thereby illuminating a mechanism for regulating oncogene expression. Collectively, our data illustrates epigenetic targeting of super enhancer-mediated oncogene addictions in UM, shedding light on an epigenetic vulnerability that can be targeted for precision therapy.