Comprehensive analysis reveals how single nucleotides contribute to noncoding RNA function in bacterial quorum sensing

Rutherford, Steven T.; Valastyan, Julie S.; Taillefumier, Thibaud; Wingreen, Ned S.; Bassler, Bonnie L.

doi:10.1073/pnas.1518958112

Cited by 27 publications

(18 citation statements)

References 45 publications

(62 reference statements)

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“…RNAs have diverse known biological roles (Garneau et al, 2007;Huang et al, 2015;Martin and Ephrussi, 2009;McManus and Graveley, 2011;Olsen et al, 1990;Rutherford et al, 2015;Sigova et al, 2015;Warf and Berglund, 2010) and both genetic and biochemical screens suggest reservoirs of functional RNA molecules we know little about. For instance, transcriptional profiling has revealed large numbers of non-coding RNA genes, with unknown functions beyond context specific expression (Eddy, 2014;Rinn and Chang, 2012).…”

Section: Introductionmentioning

confidence: 99%

3D RNA and Functional Interactions from Evolutionary Couplings

Weinreb¹,

Riesselman²,

Ingraham³

et al. 2016

Cell

162

207

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Summary Non-coding RNAs are ubiquitous, but the discovery of new RNA gene sequences far outpaces research on their structure and functional interactions. We mine the evolutionary sequence record to derive precise information about function and structure of RNAs and RNA-protein complexes. As in protein structure prediction, we use maximum entropy global probability models of sequence co-variation to infer evolutionarily constrained nucleotide-nucleotide interactions within RNA molecules, and nucleotide-amino acid interactions in RNA-protein complexes. The predicted contacts allow all-atom blinded 3D structure prediction at good accuracy for several known RNA structures and RNA-protein complexes. For unknown structures, we predict contacts in 160 non-coding RNA families. Beyond 3D structure prediction, evolutionary couplings help identify important functional interactions, e.g., at switch points in riboswitches and at a complex nucleation site in HIV. Aided by accelerating sequence accumulation, evolutionary coupling analysis can accelerate the discovery of functional interactions and 3D structures involving RNA.

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Section: Introductionmentioning

confidence: 99%

3D RNA and Functional Interactions from Evolutionary Couplings

Weinreb¹,

Riesselman²,

Ingraham³

et al. 2016

Cell

162

207

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“…In bacteria, the largest class of posttranscriptional regulators is represented by the sRNAs that associate with the Hfq protein (10,11). This RNA chaperone both stabilizes bound sRNAs and helps them regulate their mRNA targets via imperfect base pairing (12)(13)(14)(15). Together, Hfq and its associated sRNAs impact the expression >20% of all genes in enteric model bacteria such as Escherichia coli and Salmonella enterica (16,17).…”

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confidence: 99%

Grad-seq guides the discovery of ProQ as a major small RNA-binding protein

Smirnov

Förstner

Holmqvist

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

269

465

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The functional annotation of transcriptomes and identification of noncoding RNA (ncRNA) classes has been greatly facilitated by the advent of next-generation RNA sequencing which, by reading the nucleotide order of transcripts, theoretically allows the rapid profiling of all transcripts in a cell. However, primary sequence per se is a poor predictor of function, as ncRNAs dramatically vary in length and structure and often lack identifiable motifs. Therefore, to visualize an informative RNA landscape of organisms with potentially new RNA biology that are emerging from microbiome and environmental studies requires the use of more functionally relevant criteria. One such criterion is the association of RNAs with functionally important cognate RNA-binding proteins. Here we analyze the full ensemble of cellular RNAs using gradient profiling by sequencing (Grad-seq) in the bacterial pathogen Salmonella enterica, partitioning its coding and noncoding transcripts based on their network of RNA-protein interactions. In addition to capturing established RNA classes based on their biochemical profiles, the Grad-seq approach enabled the discovery of an overlooked large collective of structured small RNAs that form stable complexes with the conserved protein ProQ. We show that ProQ is an abundant RNA-binding protein with a wide range of ligands and a global influence on Salmonella gene expression. Given its generic ability to chart a functional RNA landscape irrespective of transcript length and sequence diversity, Grad-seq promises to define functional RNA classes and major RNA-binding proteins in both model species and genetically intractable organisms.small RNA | noncoding RNA | RNA-protein interaction | ProQ | Hfq

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“…In particular, sRNAs that depend on the global RNA-binding proteins (RBPs) Hfq and ProQ (Holmqvist & Vogel, 2018), contain short 'seed' regions of 8-12 highly conserved bases that disproportionately contribute to target search and pairing (Gorski, Vogel, & Doudna, 2017). Systematic analyses of sRNA seed regions have demonstrated high selectivity in mRNA recognition (Balbontin, Fiorini, Figueroa-Bossi, Casadesus, & Bossi, 2010;Kawamoto, Koide, Morita, & Aiba, 2006;Papenfort, Bouvier, Mika, Sharma, & Vogel, 2010;Rutherford, Valastyan, Taillefumier, Wingreen, & Bassler, 2015), to the degree that the seed can distinguish between two similar mRNAs at the level of a single hydrogen bond whereby a G:C and G:U pair differ (Papenfort, Podkaminski, Hinton, & Vogel, 2012). The seed can be grafted onto an unrelated sRNA and will still recognize the original targets (Bouvier et al, 2008;Fröhlich, Papenfort, Fekete, & Vogel, 2013;Papenfort et al, 2010).…”

Section: Aso Design For Targeting In Complex Communitiesmentioning

confidence: 99%

An RNA biology perspective on species‐specific programmable RNA antibiotics

Vogel

2020

Molecular Microbiology

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Our body is colonized by a vast array of bacteria the sum of which forms our microbiota. The gut alone harbors >1,000 bacterial species. An understanding of their individual or synergistic contributions to human health and disease demands means to interfere with their functions on the species level. Most of the currently available antibiotics are broad‐spectrum, thus too unspecific for a selective depletion of a single species of interest from the microbiota. Programmable RNA antibiotics in the form of short antisense oligonucleotides (ASOs) promise to achieve precision manipulation of bacterial communities. These ASOs are coupled to small peptides that carry them inside the bacteria to silence mRNAs of essential genes, for example, to target antibiotic‐resistant pathogens as an alternative to standard antibiotics. There is already proof‐of‐principle with diverse bacteria, but many open questions remain with respect to true species specificity, potential off‐targeting, choice of peptides for delivery, bacterial resistance mechanisms and the host response. While there is unlikely a one‐fits‐all solution for all microbiome species, I will discuss how recent progress in bacterial RNA biology may help to accelerate the development of programmable RNA antibiotics for microbiome editing and other applications.

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Comprehensive analysis reveals how single nucleotides contribute to noncoding RNA function in bacterial quorum sensing

Cited by 27 publications

References 45 publications

3D RNA and Functional Interactions from Evolutionary Couplings

3D RNA and Functional Interactions from Evolutionary Couplings

Grad-seq guides the discovery of ProQ as a major small RNA-binding protein

An RNA biology perspective on species‐specific programmable RNA antibiotics

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