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The transcription factor DUX4 orchestrates translational reprogramming by broadly suppressing translation efficiency

Danielle C Hamm1, Ellen M Paatela1,2, Sean R Bennett1

  • 1Human Biology Division, Fred Hutchinson Cancer Center, Seattle, Washington State, United States of America.

Plos Biology
|September 25, 2023
PubMed

Insights

The double homeobox protein 4 (DUX4) transcription factor broadly regulates protein synthesis, suppressing cellular proteomes while promoting early developmental programs. This impacts cell fate, facioscapulohumeral muscular dystrophy (FSHD), and cancer.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Developmental Biology

Background:

  • Translational control is crucial for cell fate determination in development, lineage specification, and cancer.
  • The transcription factor double homeobox protein 4 (DUX4) is implicated in human embryonic development and diseases like facioscapulohumeral muscular dystrophy (FSHD).

Purpose of the Study:

  • To investigate the role of DUX4 in regulating cellular proteome through translational control.
  • To identify specific mRNA targets affected by DUX4-mediated translational regulation.

Main Methods:

  • Analysis of translation initiation and elongation factors in DUX4-expressing human myoblasts.
  • Genome-wide translation profiling (ribosome profiling) to identify DUX4-affected mRNAs.
  • Assessment of DUX4 expression in FSHD myotubes and cancer cell lines.

Main Results:

  • DUX4 expression disrupts translation initiation and elongation factors.
  • DUX4 selectively inhibits translation of mRNAs encoding antigen presentation factors and muscle proteins.
  • DUX4 robustly translates its own induced mRNAs, promoting an early developmental program.
  • DUX4 correlates with reduced protein synthesis and MHC-I presentation in FSHD and cancer cells.

Conclusions:

  • DUX4 orchestrates cell state conversion by globally suppressing the proteome.
  • DUX4 maintains translation of its target mRNAs to drive an early developmental program.
  • DUX4's translational control mechanisms are relevant to FSHD pathogenesis and cancer immune evasion.

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