Antagonism among DUX family members evolved from an ancestral toxic single homeodomain protein
Darko Bosnakovski,
Erik A. Toso,
Elizabeth T. Ener,
Micah D. Gearhart,
Lulu Yin,
Felipe F. Lüttmann,
Alessandro Magli,
Ke Shi,
Johnny Kim,
Hideki Aihara,
Michael Kyba
Affiliations
Darko Bosnakovski
Lillehei Heart Institute, University of Minnesota, Minneapolis, MN 55455, USA; Department of Pediatrics, University of Minnesota, Minneapolis, MN 55455, USA
Erik A. Toso
Lillehei Heart Institute, University of Minnesota, Minneapolis, MN 55455, USA; Department of Pediatrics, University of Minnesota, Minneapolis, MN 55455, USA
Elizabeth T. Ener
Lillehei Heart Institute, University of Minnesota, Minneapolis, MN 55455, USA; Department of Pediatrics, University of Minnesota, Minneapolis, MN 55455, USA
Micah D. Gearhart
Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, MN 55455, USA
Lulu Yin
Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN 55455, USA
Felipe F. Lüttmann
Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
Alessandro Magli
Department of Cardiology, University of Minnesota, Minneapolis, MN 55455, USA
Ke Shi
Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN 55455, USA
Johnny Kim
Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany; The Center for Cardiovascular Regeneration and Immunology at TRON – Translational Oncology, Johannes Gutenberg-University Mainz, Mainz, Germany
Hideki Aihara
Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN 55455, USA
Michael Kyba
Lillehei Heart Institute, University of Minnesota, Minneapolis, MN 55455, USA; Department of Pediatrics, University of Minnesota, Minneapolis, MN 55455, USA; Corresponding author
Summary: Double homeobox (DUX) genes are unique to eutherian mammals, expressed transiently during zygotic genome activation (ZGA) and involved in facioscapulohumeral muscular dystrophy (FSHD) and cancer when misexpressed. We evaluate the 3 human DUX genes and the ancestral single homeobox gene sDUX from the non-eutherian mammal, platypus, and find that DUX4 cytotoxicity is not shared with DUXA or DUXB, but surprisingly is shared with platypus sDUX, which binds DNA as a homodimer and activates numerous ZGA genes and long terminal repeat (LTR) elements. DUXA, although transcriptionally inactive, has DNA binding overlap with DUX4, and DUXA-VP64 activates DUX4 targets and is cytotoxic. DUXA competition antagonizes the activity of DUX4 on its target genes, including in FSHD patient cells. Since DUXA is a DUX4 target gene, this competition potentiates feedback inhibition, constraining the window of DUX4 activity. The DUX gene family therefore comprises antagonistic members of opposing function, with implications for their roles in ZGA, FSHD, and cancer.
