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Antagonism among DUX family members evolved from an ancestral toxic single homeodomain protein

Darko Bosnakovski1,2, Erik A Toso1,2, Elizabeth T Ener1,2

  • 1Lillehei Heart Institute, University of Minnesota, Minneapolis, MN 55455, USA.

Biorxiv : the Preprint Server for Biology
|January 30, 2023
PubMed

Insights

Platypus sDUX and human DUXA exhibit surprising DUX4-like activities, including cytotoxicity and inhibition of myogenesis. DUXA acts as a feedback inhibitor of DUX4, revealing opposing functions within the DUX gene family.

Area of Science:

  • Genetics and Molecular Biology
  • Evolutionary Biology

Background:

  • Double homeobox (DUX) genes are unique to eutherian mammals and transiently expressed during zygotic genome activation (ZGA).
  • Misexpression of the canonical DUX gene, DUX4, is implicated in facioscapulohumeral muscular dystrophy (FSHD) and cancer.
  • Understanding the evolutionary and functional relationships of DUX genes is crucial for deciphering their roles in development and disease.

Approach:

  • Comparative analysis of human DUX genes (DUXA, DUXB, DUX4) and the platypus sDUX gene.
  • Functional studies in human myoblasts to assess cytotoxicity, myogenesis inhibition, and target gene induction.
  • Investigation of DUXA's transcriptional activity, DNA binding, chromatin accessibility, and interaction with DUX4.
  • Assessment of DUXA's potential to antagonize DUX4 activity in FSHD patient cells.

Key Points:

  • Platypus sDUX shares DUX4-like activities, including cytotoxicity and induction of ZGA genes, via homodimer DNA binding.
  • DUXA lacks intrinsic transcriptional activity but binds DNA and influences chromatin accessibility similarly to DUX4 and sDUX.
  • DUXA can be engineered into a DUX4-like cytotoxic factor and acts as a competitive inhibitor of DUX4.
  • DUXA, an early DUX4 target, provides feedback inhibition, limiting DUX4 activity.

Conclusions:

  • Platypus sDUX is cytotoxic and inhibits myogenic differentiation, mirroring some DUX4 functions.
  • DUXA's target genes substantially overlap with DUX4's, and it can acquire DUX4-like toxicity when fused to a transactivation domain.
  • DUXA functions as a competitive inhibitor of DUX4, suggesting cross-regulation within the DUX gene family.
  • The DUX gene family comprises members with opposing functions, impacting ZGA, FSHD, and cancer biology.

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