Bosnakovski Darko, Toso Erik A, Ener Elizabeth T, Gearhart Micah D, Yin Lulu, Lüttmann Felipe F, Magli Alessandro, Shi Ke, Kim Johnny, Aihara Hideki, Kyba Michael
Lillehei Heart Institute, University of Minnesota, Minneapolis, MN 55455, USA.
Department of Pediatrics, University of Minnesota, Minneapolis, MN 55455, USA.
iScience. 2023 Sep 2;26(10):107823. doi: 10.1016/j.isci.2023.107823. eCollection 2023 Oct 20.
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.
双同源盒（DUX）基因是真兽亚纲哺乳动物所特有的，在合子基因组激活（ZGA）过程中短暂表达，异常表达时会导致面肩肱型肌营养不良（FSHD）和癌症。我们评估了3个人类DUX基因以及来自非真兽亚纲哺乳动物鸭嘴兽的祖先单同源盒基因sDUX，发现DUX4的细胞毒性并非DUXA或DUXB所共有，但令人惊讶的是，它与鸭嘴兽sDUX共有，后者作为同二聚体结合DNA并激活众多ZGA基因和长末端重复序列（LTR）元件。DUXA虽然转录无活性，但与DUX4存在DNA结合重叠，并且DUXA-VP64可激活DUX4靶点并具有细胞毒性。DUXA竞争可拮抗DUX4对其靶基因的活性，包括在FSHD患者细胞中。由于DUXA是DUX4的靶基因，这种竞争增强了反馈抑制，限制了DUX4的活性窗口。因此，DUX基因家族包含功能相反的拮抗成员，这对它们在ZGA、FSHD和癌症中的作用具有重要意义。
