TY - JOUR
T1 - Antagonism among DUX family members evolved from an ancestral toxic single homeodomain protein
AU - Bosnakovski, Darko
AU - Toso, Erik A.
AU - Ener, Elizabeth T.
AU - Gearhart, Micah D.
AU - Yin, Lulu
AU - Lüttmann, Felipe F.
AU - Magli, Alessandro
AU - Shi, Ke
AU - Kim, Johnny
AU - Aihara, Hideki
AU - Kyba, Michael
N1 - Publisher Copyright:
© 2023 The Authors
PY - 2023/10/20
Y1 - 2023/10/20
N2 - 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.
AB - 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.
KW - Developmental genetics
KW - Evolutionary developmental biology
KW - Molecular interaction
KW - Molecular toxicology
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UR - http://www.scopus.com/inward/citedby.url?scp=85171352503&partnerID=8YFLogxK
U2 - 10.1016/j.isci.2023.107823
DO - 10.1016/j.isci.2023.107823
M3 - Article
C2 - 37744032
AN - SCOPUS:85171352503
SN - 2589-0042
VL - 26
JO - iScience
JF - iScience
IS - 10
M1 - 107823
ER -
