Merkel cell polyomavirus activates LSD1-mediated blockade of non-canonical BAF to regulate transformation and tumorigenesis

Merkel cell carcinoma (MCC), a neuroendocrine cancer of the skin, is caused by integration of Merkel cell polyomavirus (MCV) and persistent expression of Large T antigen (LT) and Small T antigen (ST). We report that ST in complex with MYCL and the EP400 complex activates expression of LSD1 (KDM1A), RCOR2, and INSM1 to repress gene expression by the lineage transcription factor ATOH1. LSD1 inhibition reduces growth of MCC in vitro and in vivo. Through a forward-genetics CRISPR-Cas9 screen, we identified an antagonistic relationship between LSD1 and the non-canonical BAF (ncBAF) chromatin remodeling complex. Changes in gene expression and chromatin accessibility caused by LSD1 inhibition could be partially rescued by BRD9 inhibition, revealing that LSD1 and ncBAF antagonistically regulate an overlapping set of genes. Our work provides mechanistic insight into the dependence of MCC on LSD1 and a tumor suppressor role for ncBAF in cancer.