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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.

Iscience
|September 25, 2023
PubMed

Insights

The double homeobox (DUX) gene family includes antagonistic members. Platypus sDUX shares cytotoxicity with DUX4, while DUXA provides feedback inhibition, impacting zygotic genome activation, facioscapulohumeral muscular dystrophy, and cancer.

Area of Science:

  • Genetics
  • Developmental Biology
  • Evolutionary Biology

Background:

  • Double homeobox (DUX) genes are unique to eutherian mammals and transiently expressed during zygotic genome activation (ZGA).
  • Misexpression of DUX genes is implicated in facioscapulohumeral muscular dystrophy (FSHD) and cancer.
  • The evolutionary origins and functional diversity of DUX genes remain incompletely understood.

Purpose of the Study:

  • To investigate the functional and evolutionary relationships between human DUX genes and the ancestral platypus sDUX gene.
  • To elucidate the mechanisms underlying DUX4-mediated cytotoxicity and its regulation.
  • To explore the potential antagonistic roles within the DUX gene family.

Main Methods:

  • Comparative analysis of human DUX genes (DUX4, DUXA, DUXB) and platypus sDUX.
  • Assessment of DNA binding, homodimerization, and transcriptional activation capabilities.
  • Evaluation of cytotoxicity and gene target activation, including in FSHD patient cells.
  • Functional assays using DUXA-VP64 fusion protein.

Main Results:

  • DUX4 cytotoxicity is shared with platypus sDUX, but not DUXA or DUXB.
  • Platypus sDUX binds DNA as a homodimer and activates ZGA genes and LTR elements.
  • DUXA exhibits DNA binding overlap with DUX4 and can activate DUX4 targets, inducing cytotoxicity.
  • DUXA antagonizes DUX4 activity on target genes, including in FSHD cells, through a feedback inhibition mechanism.

Conclusions:

  • The DUX gene family comprises members with opposing functions, acting antagonistically.
  • DUXA acts as a feedback inhibitor of DUX4, constraining its activity window.
  • These findings have significant implications for understanding DUX gene roles in ZGA, FSHD, and cancer.
Keywords:
Developmental geneticsEvolutionary developmental biologyMolecular interactionMolecular toxicology

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