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A post-transcriptional regulatory code for mRNA stability during the zebrafish maternal-to-zygotic transition

View ORCID ProfileCharles E. Vejnar, Mario Abdel Messih, Carter M. Takacs, Valeria Yartseva, Panos Oikonomou, Romain Christiano, Marlon Stoeckius, Stephanie Lau, Miler T. Lee, Jean-Denis Beaudoin, Hiba Darwich-Codore, Tobias C. Walther, Saeed Tavazoie, Daniel Ci- fuentes, Antonio J. Giraldez
doi: https://doi.org/10.1101/292441
Charles E. Vejnar
1Department of Genetics, Yale University School of Medicine, New Haven, CT 06510 USA
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  • ORCID record for Charles E. Vejnar
Mario Abdel Messih
1Department of Genetics, Yale University School of Medicine, New Haven, CT 06510 USA
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Carter M. Takacs
1Department of Genetics, Yale University School of Medicine, New Haven, CT 06510 USA
4University of New Haven, West Haven, CT 06516 USA
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Valeria Yartseva
1Department of Genetics, Yale University School of Medicine, New Haven, CT 06510 USA
5Department of Molecular Biology, Genentech, Inc. South San Francisco, CA 94080 USA
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Panos Oikonomou
6Department of Systems Biology, Columbia University, New York, NY 10032 USA
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Romain Christiano
7Department of Genetics and Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, MA 02115 USA
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Marlon Stoeckius
1Department of Genetics, Yale University School of Medicine, New Haven, CT 06510 USA
8New York Genome Center, New York, NY 10013 USA
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Stephanie Lau
1Department of Genetics, Yale University School of Medicine, New Haven, CT 06510 USA
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Miler T. Lee
1Department of Genetics, Yale University School of Medicine, New Haven, CT 06510 USA
9Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA 15260 USA
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Jean-Denis Beaudoin
1Department of Genetics, Yale University School of Medicine, New Haven, CT 06510 USA
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Hiba Darwich-Codore
1Department of Genetics, Yale University School of Medicine, New Haven, CT 06510 USA
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Tobias C. Walther
7Department of Genetics and Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, MA 02115 USA
10Department of Cell Biology, Harvard Medical School, Boston, MA 02115 USA
11Broad Institute of Harvard and MIT, Cambridge, MA 02124 USA
12Howard Hughes Medical Institute, Boston, MA 02115 USA
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Saeed Tavazoie
13Department of Biochemistry and Molecular Biophysics, and Department of Systems Biology, Columbia University, New York, NY 10032 USA
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Daniel Ci- fuentes
1Department of Genetics, Yale University School of Medicine, New Haven, CT 06510 USA
14Department of Biochemistry, Boston University School of Medicine, Boston, MA 02118
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  • For correspondence: dcb@bu.edu antonio.giraldez@yale.edu
Antonio J. Giraldez
1Department of Genetics, Yale University School of Medicine, New Haven, CT 06510 USA
2Yale Stem Cell Center, Yale University School of Medicine, New Haven, CT 06510 USA
3Yale Cancer Center, Yale University School of Medicine, New Haven, CT 06510 USA
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  • For correspondence: dcb@bu.edu antonio.giraldez@yale.edu
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Abstract

Post-transcriptional regulation is crucial to shape gene expression. During the Maternal-to-Zygotic Transition (MZT), thousands of maternal transcripts are regulated upon fertilization and genome activation. Transcript stability can be influenced by cis-elements and trans-factors, but how these inputs are integrated to determine the overall mRNA stability is unclear. Here, we show that most transcripts are under combinatorial regulation by multiple decay pathways during zebrafish MZT. To identify cis-regulatory elements, we performed a massively parallel reporter assay for stability-influencing sequences, which revealed that 3’-UTR poly-U motifs are associated with mRNA stability. In contrast, miR-430 target sequences, UAUUUAUU AU-rich elements (ARE), CCUC and CUGC elements emerged as the main destabilizing motifs in the embryo, with miR-430 and AREs causing mRNA deadenylation in a genome activation-dependent manner. To identify the trans-factors interacting with these cis-elements, we comprehensively profiled RNA-protein interactions and their associated regulatory activities across the transcriptome during the MZT. We find that poly-U binding proteins are preferentially associated with 3’-UTR sequences and stabilizing motifs, and that antagonistic sequence contexts for poly-C and poly-U binding proteins shape the binding landscape and magnitude of regulation across the transcriptome. Finally, we integrate these regulatory motifs into a machine learning model that accurately predicts the stability of mRNA reporters in vivo. Our findings reveal how mechanisms of post-transcriptional regulation are coordinated to direct changes in mRNA stability within the early zebrafish embryo.

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Posted March 30, 2018.
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A post-transcriptional regulatory code for mRNA stability during the zebrafish maternal-to-zygotic transition
Charles E. Vejnar, Mario Abdel Messih, Carter M. Takacs, Valeria Yartseva, Panos Oikonomou, Romain Christiano, Marlon Stoeckius, Stephanie Lau, Miler T. Lee, Jean-Denis Beaudoin, Hiba Darwich-Codore, Tobias C. Walther, Saeed Tavazoie, Daniel Ci- fuentes, Antonio J. Giraldez
bioRxiv 292441; doi: https://doi.org/10.1101/292441
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A post-transcriptional regulatory code for mRNA stability during the zebrafish maternal-to-zygotic transition
Charles E. Vejnar, Mario Abdel Messih, Carter M. Takacs, Valeria Yartseva, Panos Oikonomou, Romain Christiano, Marlon Stoeckius, Stephanie Lau, Miler T. Lee, Jean-Denis Beaudoin, Hiba Darwich-Codore, Tobias C. Walther, Saeed Tavazoie, Daniel Ci- fuentes, Antonio J. Giraldez
bioRxiv 292441; doi: https://doi.org/10.1101/292441

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