Abstract
The complexity of multicellular organisms requires precise spatiotemporal regulation of gene expression during development. We find that in the nematode Caenorhabditis elegans approximately 2,000 transcripts undergo expression oscillations synchronized with larval transitions while thousands of genes are expressed in temporal gradients, similar to known timing regulators. By counting transcripts in individual worms, we show that pulsatile expression of the microRNA (miRNA) lin-4 maintains the temporal gradient of its target lin-14 by dampening its expression oscillations. Our results demonstrate that this insulation is optimal when pulsatile expression of the miRNA and its target is synchronous. We propose that such a miRNA-mediated incoherent feed-forward loop is a potent filter that prevents the propagation of potentially deleterious fluctuations in gene expression during the development of an organism.
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Acknowledgements
We thank V. Ambros, H.R. Horvitz, G. Ruvkun and J. Gore for helpful discussions and advice. We thank S. Itzkovitz, J.P. Junker, G. Neuert, J. van Zon, A. Sahay and C. Engert for a critical reading of the manuscript. We thank the Massachusetts Institute of Technology (MIT) BioMicro Center for Illumina sample preparation and sequencing experiments. We also thank the Biopolymers & Proteomics Core Facility of the MIT Koch Institute for Integrative Cancer Research for probe purification. Several nematode strains used in this work were provided by H.R. Horvitz (Massachusetts Institute of Technology) and A. Fire (Stanford University) and the Caenorhabditis Genetics Center, which is funded by the US National Institutes of Health (NIH) and National Center for Research Resources (NCRR). This work was supported by the US NIH/National Cancer Institute Physical Sciences Oncology Center at MIT (U54CA143874), a US NIH Pioneer award (8 DP1 CA174420-05), a European Research Council Advanced grant (ERC-AdG 294325-GeneNoiseControl) and a Green Cross Corp. (Republic of Korea) Mogam Science Scholarship.
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D.h.K. and A.v.O. conceived the project and designed the experiments. D.h.K. performed the experiments. D.h.K., D.G. and A.v.O. analyzed the data and wrote the manuscript.
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Supplementary Text and Figures
Supplementary Note and Supplementary Figures 1–14 (PDF 6048 kb)
Supplementary Table 1
Assignment of genes to expression clusters for clusters genes (XLSX 271 kb)
Supplementary Table 2
A full list of GO terms enriched in clusters of coexpressed genes (XLSX 300 kb)
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Kim, D., Grün, D. & van Oudenaarden, A. Dampening of expression oscillations by synchronous regulation of a microRNA and its target. Nat Genet 45, 1337–1344 (2013). https://doi.org/10.1038/ng.2763
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DOI: https://doi.org/10.1038/ng.2763
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