DUX4 orchestrates translational reprograming by broadly suppressing translation efficiency [polysome-seq]

DUX4, an embryonic transcription factor normally silenced in somatic tissues, was recently shown to reduce major histocompatibility complex I (MHC-I) and promote immune evasion in numerous cancer types. We report that transient expression of DUX4 results in the long-term suppression of interferon-gamma induction of MHC-I and the immunoproteasome. Brief expression of transcriptionally active DUX4 leads to a prolonged decrease in protein synthesis, altering the activity of translation initiation regulators eIF2a, eIF4E, 4EBP1, and translation elongation factor eEF2. Translational profiling identified mRNAs susceptible to DUX4-induced inhibition of translation initiation and elongation, including mRNAs encoding antigen presentation factors. We show that DUX4 orchestrates translational reprogramming by broadly attenuating protein synthesis while inducing the expression of RNAs encoding early embryonic proteins that are translationally up regulated and predicted to be less vulnerable to translational inhibition. Endogenous expression of DUX4 and its target genes in FSHD muscle cells and SuSa germinoma cells also correlates with suppression of protein synthesis and reduced MHC-I presentation. Our findings reveal a novel role of DUX4 in modulating translational control to reshape the cellular translatome with important implications for development and disease. Comparative polysome profiling RNA-seq analysis for MB135iDUX4 myoblasts treated with a DUX4 pulse+IFNg harvested at 68h or with IFNg treatment alone.