Polyomavirus and neuroendocrine regulomes converge to establish tumor dependencies

Merkel Cell carcinoma (MCC) is an aggressive neuroendocrine skin cancer often driven by Merkel cell polyomavirus T antigens. The epigenomic mechanisms driving MCC are poorly understood. We show that virus positive MCC (VP-MCC) super enhancer networks are committed to and controlled by lineage-specific neuroendocrine transcription factors (TFs) including LHX3, ISL1, ATOH1, INSM1, SOX2 and POU4F3. These VP-MCC TFs are central to core regulatory (CR) transcriptional circuitry, essential for growth, and co-bind enhancers with polyomavirus small T antigen. We establish that T antigen expression is directly regulated by LHX3 and ISL1, establishing a positive feedback autoregulatory circuitry for a neuroendocrine state. Virus positive and virus negative MCC cell lines were assayed for enhancers by H3K27ac ChIP-seq (3 VN MCC and 4 VP MCC), open chromatin by DNase hypersensitivity (same cell lines, most in duplicate), and TF binding by ChIP-seq for the top 6 core regulatory TFs (2 cell lines).