Department of Integrated Biosciences, Graduate School of Frontier Sciences, The University of Tokyo, Seimei-Building 302, 5-1-5 Kashiwanoha, Kashiwa, 277-8562, Japan.
Published: November 2020
AI Article Synopsis
Article Abstract
After fertilization, the zygotic genome is activated through two phases, minor zygotic activation (ZGA) and major ZGA. Recently, it was suggested that DUX is expressed during minor ZGA and activates some genes during major ZGA. However, it has not been proven that Dux is expressed during minor ZGA and functions to activate major ZGA genes, because there are several Dux paralogs that may be expressed in zygotes instead of Dux. In this study, we found that more than a dozen Dux paralogs, as well as Dux, are expressed during minor ZGA. Overexpression of some of these genes induced increased expression of major ZGA genes. These results suggest that multiple Dux paralogs are expressed to ensure a sufficient amount of functional Dux and its paralogs which are generated during a short period of minor ZGA with a low transcriptional activity. The mechanism by which multiple Dux paralogs are expressed is discussed.
DUX4 is linked to facioscapulohumeral muscular dystrophy, but its impact on Duchenne muscular dystrophy (DMD) is uncertain; research involves Dux, the mouse version of DUX4.
Experiments on Dux mdx mice demonstrated that removing Dux improved muscle strength, endurance, and reduced harmful effects like fibrosis and inflammation.
The absence of Dux also boosted muscle satellite cell growth and survival by raising levels of the antioxidant molecule Nrf2 in the affected mice.
Department of Integrated Biosciences, Graduate School of Frontier Sciences, The University of Tokyo, Seimei-Building 302, 5-1-5 Kashiwanoha, Kashiwa, 277-8562, Japan.
After fertilization, the zygotic genome is activated through two phases, minor zygotic activation (ZGA) and major ZGA. Recently, it was suggested that DUX is expressed during minor ZGA and activates some genes during major ZGA. However, it has not been proven that Dux is expressed during minor ZGA and functions to activate major ZGA genes, because there are several Dux paralogs that may be expressed in zygotes instead of Dux.
After fertilization of the transcriptionally silent oocyte, expression from both parental chromosomes is launched through zygotic genome activation (ZGA), occurring in the mouse at the 2-cell (2C) stage. Among the first elements to be transcribed are the gene, the product of which induces a wide array of ZGA genes, and a subset of evolutionary recent LINE-1 retrotransposons that regulate chromatin accessibility in the early embryo. The maternally inherited factors that activate and LINE-1 transcription have so far remained unknown.
D4Z4 repeats are present in at least 11 different mammalian species, including humans and mice. Each repeat contains an open reading frame encoding a double homeodomain (DUX) family transcription factor. Aberrant expression of the D4Z4 ORF called DUX4 is associated with the pathogenesis of Facioscapulohumeral muscular dystrophy (FSHD).
Recent molecular advances have identified a novel, clinically aggressive subgroup of undifferentiated round cell sarcomas defined molecularly by oncogenic fusion of the gene, CIC, and either DUX4 or its paralog, DUX4L, herein termed CIC-DUX sarcomas. Morphologically, CIC-DUX sarcomas are round cell sarcomas with high-grade nuclear features, including vesicular chromatin and nucleoli, patchy clear cell foci, myxoid change, and necrosis. Here, we studied a cohort of 10 cases, including 6 newly identified cases, 2 with paired metastases.
