Obox4 promotes zygotic genome activation upon loss of Dux

Once fertilized, mouse zygotes rapidly proceed to zygotic genome activation (ZGA), during which long terminal repeats (LTRs) of murine endogenous retroviruses with leucine tRNA primer (MERVL) are activated by a conserved homeodomain-containing transcription factor, DUX. However, Dux-knockout embryos...

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Published inbioRxiv
Main Authors Guo, Youjia, Kitano, Tomohiro, Inoue, Kimiko, Murano, Kensaku, Hirose, Michiko, Li, Ten D, Sakashita, Akihiko, Ishizu, Hirotsugu, Narumi Ogonuki, Matoba, Shogo, Sato, Masayuki, Ogura, Atsuo, Siomi, Haruhiko
Format Paper
LanguageEnglish
Published Cold Spring Harbor Cold Spring Harbor Laboratory Press 04.01.2024
Subjects
Embryogenesis
Fertility
Genomes
Histones
Homeobox
Transcription factors
Transcriptomes
Transfer RNA
tRNA Leu
tRNA Lys
Zygotes
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Summary:Once fertilized, mouse zygotes rapidly proceed to zygotic genome activation (ZGA), during which long terminal repeats (LTRs) of murine endogenous retroviruses with leucine tRNA primer (MERVL) are activated by a conserved homeodomain-containing transcription factor, DUX. However, Dux-knockout embryos produce fertile mice, suggesting that ZGA is redundantly driven by an unknown factor(s). Here we present multiple lines of evidence that the multicopy homeobox gene, Obox4, encodes a transcription factor that is highly expressed in mouse 2-cell embryos and redundantly drives ZGA. Genome-wide profiling revealed that OBOX4 specifically binds and activates MERVL LTRs as well as a subset of murine endogenous retroviruses with lysine tRNA primer (MERVK) LTRs. Depletion of Obox4 is tolerated by embryogenesis, whereas concomitant Obox4/Dux depletion markedly compromises embryonic development. Our study identified OBOX4 as a transcription factor that provides genetic redundancy to pre-implantation development.Competing Interest StatementThe authors have declared no competing interest.Footnotes* Produced Dux and Obox4 single/double knockout mice. Added fertility data, preimplantation development monitoring, transcriptome profiling analysis of single and double KO embryos. Removed histone modification analysis in TBLCs for better coherence of the manuscript.
DOI:10.1101/2022.07.04.498763