Genome wide analysis of 3′ UTR sequence elements and proteins regulating mRNA stability during maternal-to-zygotic transition in zebrafish
- Charles E. Vejnar1,15,
- Mario Abdel Messih1,15,
- Carter M. Takacs1,2,15,
- Valeria Yartseva1,3,15,
- Panos Oikonomou4,15,
- Romain Christiano5,
- Marlon Stoeckius1,6,
- Stephanie Lau1,
- Miler T. Lee1,7,
- Jean-Denis Beaudoin1,
- Damir Musaev1,
- Hiba Darwich-Codore1,
- Tobias C. Walther5,8,9,10,
- Saeed Tavazoie11,
- Daniel Cifuentes1,12 and
- Antonio J. Giraldez1,13,14
- 1Department of Genetics, Yale University School of Medicine, New Haven, Connecticut 06510, USA;
- 2University of New Haven, West Haven, Connecticut 06516, USA;
- 3Department of Neuroscience, Genentech, Incorporated, South San Francisco, California 94080, USA;
- 4Department of Systems Biology, Columbia University, New York, New York 10032, USA;
- 5Department of Genetics and Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts 02115, USA;
- 6New York Genome Center, New York, New York 10013, USA;
- 7Department of Biological Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, USA;
- 8Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA;
- 9Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02124, USA;
- 10Howard Hughes Medical Institute, Boston, Massachusetts 02115, USA;
- 11Department of Biochemistry and Molecular Biophysics, and Department of Systems Biology, Columbia University, New York, New York 10032, USA;
- 12Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts 02118, USA;
- 13Yale Stem Cell Center, Yale University School of Medicine, New Haven, Connecticut 06510, USA;
- 14Yale Cancer Center, Yale University School of Medicine, New Haven, Connecticut 06510, USA
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↵15 These authors contributed equally to this work.
Abstract
Posttranscriptional regulation plays a crucial role in shaping gene expression. During the maternal-to-zygotic transition (MZT), thousands of maternal transcripts are regulated. However, how different cis-elements and trans-factors are integrated to determine mRNA stability remains poorly understood. Here, we show that most transcripts are under combinatorial regulation by multiple decay pathways during zebrafish MZT. By using a massively parallel reporter assay, we identified cis-regulatory sequences in the 3′ UTR, including U-rich motifs that are associated with increased mRNA stability. In contrast, miR-430 target sequences, UAUUUAUU AU-rich elements (ARE), CCUC, and CUGC elements emerged as destabilizing motifs, with miR-430 and AREs causing mRNA deadenylation upon genome activation. We identified trans-factors by profiling RNA–protein interactions and found that poly(U)-binding proteins are preferentially associated with 3′ UTR sequences and stabilizing motifs. We show that this activity is antagonized by C-rich motifs and correlated with protein binding. Finally, we integrated these regulatory motifs into a machine learning model that predicts reporter mRNA stability in vivo.
Footnotes
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[Supplemental material is available for this article.]
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Article published online before print. Article, supplemental material, and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.245159.118.
- Received October 16, 2018.
- Accepted June 7, 2019.
This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genome.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
