DUX-family Transcription Factors Regulate Zygotic Genome Activation in Placental Mammals

Overview

Journal Nat Genet

Specialty Genetics

Date 2017 May 2

PMID 28459456

Citations 307

Authors

Alberto de Iaco

Evarist Planet

Andrea Coluccio

Sonia Verp

Julien Duc

Didier Trono

Affiliations

Soon will be listed here.

Abstract

In animal embryos, transcription is mostly silent for several cell divisions, until the release of the first major wave of embryonic transcripts through so-called zygotic genome activation (ZGA). Maternally provided ZGA-triggering factors have been identified in Drosophila melanogaster and Danio rerio, but their mammalian homologs are still undefined. Here, we provide evidence that the DUX family of transcription factors is essential to this process in mice and potentially in humans. First, human DUX4 and mouse Dux are both expressed before ZGA in their respective species. Second, both orthologous proteins bind the promoters of ZGA-associated genes and activate their transcription. Third, Dux knockout in mouse embryonic stem cells (mESCs) prevents the cells from cycling through a 2-cell-like state. Finally, zygotic depletion of Dux leads to impaired early embryonic development and defective ZGA. We conclude that DUX-family proteins are key inducers of zygotic genome activation in placental mammals.

Citing Articles

Trps1 regulates mouse zygotic genome activation and preimplantation embryo development via the PDE4D/AKT/CREB signaling pathway.

Jiang X, Xu W, Sun J, Lin J, Lin Z, Lian X Cell Biol Toxicol. 2025; 41(1):48.

PMID: 39979480 PMC: 11842480. DOI: 10.1007/s10565-025-09999-1.

SMARCAD1 and TOPBP1 contribute to heterochromatin maintenance at the transition from the 2C-like to the pluripotent state.

Sebastian-Perez R, Nakagawa S, Tu X, Aranda S, Pesaresi M, Gomez-Garcia P Elife. 2025; 12.

PMID: 39969508 PMC: 11839162. DOI: 10.7554/eLife.87742.

A CRISPR/Cas9-based kinome screen identifies ErbB signaling as a new regulator of human naïve pluripotency and totipotency.

Li J, Lin X, Xie L, Zhao J, Han C, Deng H Life Med. 2025; 2(4):lnad037.

PMID: 39872545 PMC: 11749542. DOI: 10.1093/lifemedi/lnad037.

Herpesviruses mimic zygotic genome activation to promote viral replication.

Neugebauer E, Walter S, Tan J, Drayman N, Franke V, van Gent M Nat Commun. 2025; 16(1):710.

PMID: 39814710 PMC: 11735616. DOI: 10.1038/s41467-025-55928-5.

The Unexplored Role of Connexin Hemichannels in Promoting Facioscapulohumeral Muscular Dystrophy Progression.

Diaz-Ubilla M, Retamal M Int J Mol Sci. 2025; 26(1.

PMID: 39796228 PMC: 11719937. DOI: 10.3390/ijms26010373.

References

Lee M, Bonneau A, Takacs C, Bazzini A, DiVito K, Fleming E . Nanog, Pou5f1 and SoxB1 activate zygotic gene expression during the maternal-to-zygotic transition. Nature. 2013; 503(7476):360-4. PMC: 3925760. DOI: 10.1038/nature12632. View

Lu F, Liu Y, Jiang L, Yamaguchi S, Zhang Y . Role of Tet proteins in enhancer activity and telomere elongation. Genes Dev. 2014; 28(19):2103-19. PMC: 4180973. DOI: 10.1101/gad.248005.114. View

Geng L, Yao Z, Snider L, Fong A, Cech J, Young J . DUX4 activates germline genes, retroelements, and immune mediators: implications for facioscapulohumeral dystrophy. Dev Cell. 2012; 22(1):38-51. PMC: 3264808. DOI: 10.1016/j.devcel.2011.11.013. View

Kolesnikov N, Hastings E, Keays M, Melnichuk O, Tang Y, Williams E . ArrayExpress update--simplifying data submissions. Nucleic Acids Res. 2014; 43(Database issue):D1113-6. PMC: 4383899. DOI: 10.1093/nar/gku1057. View

Young J, Whiddon J, Yao Z, Kasinathan B, Snider L, Geng L . DUX4 binding to retroelements creates promoters that are active in FSHD muscle and testis. PLoS Genet. 2013; 9(11):e1003947. PMC: 3836709. DOI: 10.1371/journal.pgen.1003947. View

Langmead B, Salzberg S . Fast gapped-read alignment with Bowtie 2. Nat Methods. 2012; 9(4):357-9. PMC: 3322381. DOI: 10.1038/nmeth.1923. View

Liang H, Nien C, Liu H, Metzstein M, Kirov N, Rushlow C . The zinc-finger protein Zelda is a key activator of the early zygotic genome in Drosophila. Nature. 2008; 456(7220):400-3. PMC: 2597674. DOI: 10.1038/nature07388. View

de Iaco A, Santoni F, Vannier A, Guipponi M, Antonarakis S, Luban J . TNPO3 protects HIV-1 replication from CPSF6-mediated capsid stabilization in the host cell cytoplasm. Retrovirology. 2013; 10:20. PMC: 3599327. DOI: 10.1186/1742-4690-10-20. View

Kim D, Pertea G, Trapnell C, Pimentel H, Kelley R, Salzberg S . TopHat2: accurate alignment of transcriptomes in the presence of insertions, deletions and gene fusions. Genome Biol. 2013; 14(4):R36. PMC: 4053844. DOI: 10.1186/gb-2013-14-4-r36. View

10.

Wu J, Huang B, Chen H, Yin Q, Liu Y, Xiang Y . The landscape of accessible chromatin in mammalian preimplantation embryos. Nature. 2016; 534(7609):652-7. DOI: 10.1038/nature18606. View

11.

Macfarlan T, Gifford W, Driscoll S, Lettieri K, Rowe H, Bonanomi D . Embryonic stem cell potency fluctuates with endogenous retrovirus activity. Nature. 2012; 487(7405):57-63. PMC: 3395470. DOI: 10.1038/nature11244. View

12.

Deng Q, Ramskold D, Reinius B, Sandberg R . Single-cell RNA-seq reveals dynamic, random monoallelic gene expression in mammalian cells. Science. 2014; 343(6167):193-6. DOI: 10.1126/science.1245316. View

13.

Law C, Chen Y, Shi W, Smyth G . voom: Precision weights unlock linear model analysis tools for RNA-seq read counts. Genome Biol. 2014; 15(2):R29. PMC: 4053721. DOI: 10.1186/gb-2014-15-2-r29. View

14.

Soufi A, Donahue G, Zaret K . Facilitators and impediments of the pluripotency reprogramming factors' initial engagement with the genome. Cell. 2012; 151(5):994-1004. PMC: 3508134. DOI: 10.1016/j.cell.2012.09.045. View

15.

Walter M, Teissandier A, Perez-Palacios R, Bourchis D . An epigenetic switch ensures transposon repression upon dynamic loss of DNA methylation in embryonic stem cells. Elife. 2016; 5. PMC: 4769179. DOI: 10.7554/eLife.11418. View

16.

Tohonen V, Katayama S, Vesterlund L, Jouhilahti E, Sheikhi M, Madissoon E . Novel PRD-like homeodomain transcription factors and retrotransposon elements in early human development. Nat Commun. 2015; 6:8207. PMC: 4569847. DOI: 10.1038/ncomms9207. View

17.

Leidenroth A, Clapp J, Mitchell L, Coneyworth D, Dearden F, Iannuzzi L . Evolution of DUX gene macrosatellites in placental mammals. Chromosoma. 2012; 121(5):489-97. DOI: 10.1007/s00412-012-0380-y. View

18.

Schulz K, Bondra E, Moshe A, Villalta J, Lieb J, Kaplan T . Zelda is differentially required for chromatin accessibility, transcription factor binding, and gene expression in the early Drosophila embryo. Genome Res. 2015; 25(11):1715-26. PMC: 4617967. DOI: 10.1101/gr.192682.115. View

19.

Yan L, Yang M, Guo H, Yang L, Wu J, Li R . Single-cell RNA-Seq profiling of human preimplantation embryos and embryonic stem cells. Nat Struct Mol Biol. 2013; 20(9):1131-9. DOI: 10.1038/nsmb.2660. View

20.

Gentleman R, Carey V, Bates D, Bolstad B, Dettling M, Dudoit S . Bioconductor: open software development for computational biology and bioinformatics. Genome Biol. 2004; 5(10):R80. PMC: 545600. DOI: 10.1186/gb-2004-5-10-r80. View