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Inference of bacterial small RNA regulatory networks and integration with transcription factor driven regulatory networks

Mario L. Arrieta-Ortiz, Christoph Hafemeister, Bentley Shuster, Nitin S. Baliga, Richard Bonneau, View ORCID ProfilePatrick Eichenberger
doi: https://doi.org/10.1101/657478
Mario L. Arrieta-Ortiz
1Center for Genomics and Systems Biology, Department of Biology, New York University, New York, NY, USA
2Institute for Systems Biology, Seattle, WA, USA
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Christoph Hafemeister
1Center for Genomics and Systems Biology, Department of Biology, New York University, New York, NY, USA
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Bentley Shuster
1Center for Genomics and Systems Biology, Department of Biology, New York University, New York, NY, USA
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Nitin S. Baliga
2Institute for Systems Biology, Seattle, WA, USA
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Richard Bonneau
1Center for Genomics and Systems Biology, Department of Biology, New York University, New York, NY, USA
3Center for Computational Biology, Flatiron Institute, New York, NY, USA
4Center for Data Science, New York University, New York, NY, USA
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  • For correspondence: pe19@nyu.edu
Patrick Eichenberger
1Center for Genomics and Systems Biology, Department of Biology, New York University, New York, NY, USA
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  • ORCID record for Patrick Eichenberger
  • For correspondence: pe19@nyu.edu
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ABSTRACT

Small non-coding RNAs (sRNAs) are key regulators of bacterial gene expression. Through complementary base pairing, sRNAs affect messenger RNA stability and translation efficiency. Here, we describe a network inference approach designed to identify sRNA-mediated regulation of transcript levels. We use existing transcriptional datasets and prior knowledge to infer sRNA regulons using our network inference tool, the Inferelator. This approach produces genome-wide gene regulatory networks that include contributions by both transcription factors and sRNAs. We show the benefits of estimating and incorporating sRNA activities into network inference pipelines. We comprehensively assess the accuracy of inferred sRNA regulons using available experimental data. We uncover 30 novel experimentally supported sRNA-mRNA interactions in Escherichia coli, outperforming previous network-based efforts. Our findings expand the role of sRNAs in the regulation of chemotaxis, oxidation-reduction processes, galactose intake, and generation of pyruvate. Additionally, our pipeline complements sequence-based sRNA-mRNA interaction prediction methods by adding a data-driven filtering step. Finally, we show the general applicability of our approach by identifying novel, experimentally supported, sRNA-mRNA interactions in Pseudomonas aeruginosa and Bacillus subtilis. Overall, our strategy generates novel insights into the functional implications of sRNA regulation in multiple bacterial species.

IMPORTANCE Individual bacterial genomes can have dozens of small non-coding RNAs with largely unexplored regulatory functions. Although bacterial sRNAs influence a wide range of biological processes, including antibiotic resistance and pathogenicity, our current understanding of sRNA-mediated regulation is far from complete. Most of the available information is restricted to a few well-studied bacterial species; and even in those species, only partial sets of sRNA targets have been characterized in detail. To close this information gap, we developed a computational strategy that takes advantage of available transcriptional data and knowledge about validated and putative sRNA-mRNA interactions. Our approach facilitates the identification of experimentally supported novel interactions while filtering out false positives. Due to its data-driven nature, our method emerges as an ideal strategy to identify biologically relevant interactions among lists of candidate sRNA-target pairs predicted in silico from sequence analysis or derived from sRNA-mRNA binding experiments.

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Posted June 03, 2019.
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Inference of bacterial small RNA regulatory networks and integration with transcription factor driven regulatory networks
Mario L. Arrieta-Ortiz, Christoph Hafemeister, Bentley Shuster, Nitin S. Baliga, Richard Bonneau, Patrick Eichenberger
bioRxiv 657478; doi: https://doi.org/10.1101/657478
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Inference of bacterial small RNA regulatory networks and integration with transcription factor driven regulatory networks
Mario L. Arrieta-Ortiz, Christoph Hafemeister, Bentley Shuster, Nitin S. Baliga, Richard Bonneau, Patrick Eichenberger
bioRxiv 657478; doi: https://doi.org/10.1101/657478

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