The transcription factor DUX4 orchestrates translational reprogramming by broadly suppressing translation efficiency and promoting expression of DUX4-induced mRNAs

Translational control is critical for cell fate transitions during development, lineage specification, and tumorigenesis. Here, we show that the transcription factor double homeobox protein 4 (DUX4), and its previously characterized transcriptional program, broadly regulates translation to change the cellular proteome. DUX4 is a key regulator of zygotic genome activation in human embryos, whereas misexpression of DUX4 causes facioscapulohumeral muscular dystrophy (FSHD) and is associated with MHC-I suppression and immune evasion in cancer. We report that translation initiation and elongation factors are disrupted downstream of DUX4 expression in human myoblasts. Genome-wide translation profiling identified mRNAs susceptible to DUX4-induced translation inhibition, including those encoding antigen presentation factors and muscle lineage proteins, while DUX4-induced mRNAs were robustly translated. Endogenous expression of DUX4 in human FSHD myotubes and cancer cell lines also correlated with reduced protein synthesis and MHC-I presentation. Our findings reveal that DUX4 orchestrates translational reprogramming by suppressing the cellular proteome while maintaining translation of DUX4-induced mRNAs to promote an early developmental program. Cellular reprogramming requires multifaceted regulation of gene expression. This study shows that DUX4 modulates multiple translational regulators to broadly suppress protein synthesis while promoting expression of DUX4-induced genes, suggesting a natural role in cell state conversion during development and a pathological role when expressed in cancer or muscular dystrophy.

Automated summary

The transcription factor DUX4 regulates translation to change the cellular proteome, and its misexpression is associated with muscular dystrophy and immune evasion in cancer.