Liaison between SNAI2 and MYOD enhances oncogenesis and suppresses differentiation in Fusion-Negative Rhabdomyosarcoma

Rhabdomyosarcoma (RMS) is a pediatric malignancy of mesenchymal origin. Fusion Negative-RMS (FN-RMS) tumors are associated with RAS-pathway activation. RMS tumors express pro-differentiation myogenic transcription factors MYOD and MYOG, yet why they are unable to differentiate is poorly understood. Here we show that SNAI2 is highly expressed in FN-RMS, is regulated by MYOD and blocks myogenic differentiation promoting growth. Molecularly, SNAI2 preferentially binds E-Box-associated enhancer elements and represses expression by dampening enhancer function. SNAI2 inhibits MYOD at a subset of myogenic enhancers associated with terminal differentiation. Functional dissection demonstrates SNAI2 suppresses a MYOG, MEF2 and CDKN1A differentiation program. SNAI2 knockdown transcriptionally mimics a chemical blockade of the mutant RAS signal in FN-RMS, providing new insight connecting the genetic and epigenetic causes of this disease. Overall design: Epignome-wide binding profiles of histone modifications and transcription factors, before and after selected disruption of SNAI2 via chemical or genetic means, in FN_RMS cell lines, by ChIP-seq. RNA-seq in 2 FN-RMS cell lines exposed to either shControl or shSNAI2. H3K27ac HiChIP of RMS cell line.