SIX1 Reprograms Myogenic Transcription Factors to Maintain the Rhabdomyosarcoma undifferentiated state

Author:

Hsu Jessica Y.ORCID,Danis Etienne P.,Nance Stephanie,O’Brien Jenean,Wessells Veronica M.,Goodspeed Andrew E.,Talbot Jared C.,Amacher Sharon L.,Jedlicka Paul,Black Joshua C.,Costello James C.ORCID,Durbin Adam D.,Artinger Kristin B.,Ford Heide L.

Abstract

SummaryRhabdomyosarcoma (RMS) is a pediatric skeletal muscle sarcoma characterized by the expression of the myogenic-lineage transcription factors (TF) MYOD1 and MYOG. Despite high expression of these TFs, RMS cells fail to terminally differentiate, suggesting the presence of factors that alter their function. Here, we demonstrate that the developmental TF, SIX1, is highly expressed in RMS and is critical to maintain a muscle progenitor-like state. SIX1 loss induces terminal differentiation of RMS cells into myotube-like cells and dramatically impedes tumor growth in vivo. We show that SIX1 maintains the RMS undifferentiated state by controlling enhancer activity and MYOD1 occupancy at loci more permissive to tumor growth over terminal muscle differentiation. Finally, we demonstrate that a gene signature derived from SIX1 loss correlates with differentiation status in RMS and predicts RMS progression in human disease. Our findings demonstrate a master regulatory role for SIX1 in the repression of RMS differentiation via genome-wide alterations in MYOD1-mediated transcription.HighlightsSIX1 prevents differentiation in RMS while it promotes differentiation during normal developmentFN-RMS are highly dependent on SIX1 for growth in both zebrafish and mouse xenograft modelsLoss of SIX1 alters the transcriptional landscape of RMS cells, inducing a growth to differentiation switchSIX1 knockdown in FN-RMS causes reduced super enhancer-based activity at stem-related genes and enhanced MYOD1 binding to differentiation loci, resulting in the activation of a myogenic differentiation programA gene signature derived from SIX1 loss strongly correlates with myogenic differentiation status and is predictive of advanced RMS.

Publisher

Cold Spring Harbor Laboratory

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