Transcriptional noise and exaptation as sources for bacterial sRNAs

Jose, Bethany R.; Geeleher, Paul; Barquist, Lars

doi:10.1042/bst20180171

Cited by 28 publications

(27 citation statements)

References 108 publications

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“…Transposable element regulation by antisense transcripts was one of the earliest discovered examples of riboregulation 71 , though it has not previously been observed at the scale implied by our RNA-seq analysis. Such antisense regulation could arise spontaneously through capture of transcriptional noise, providing a parsimonious alternative to transcriptional control 72 . It is unclear whether these untranslated transcripts have some function in Ot, or whether they are purely selfish DNA elements that Ot has been unable to dispose of due to its small population size.…”

Section: Discussionmentioning

confidence: 99%

Dual RNA-seq provides insight into the biology of the neglected intracellular human pathogenOrientia tsutsugamushi

Mika-Gospodorz

Giengkam

Westermann

et al. 2019

Preprint

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29Emerging and neglected diseases pose challenges as their biology is frequently poorly understood, and 30 genetic tools often do not exist to manipulate the responsible pathogen. Organism agnostic sequencing 31 technologies offer a promising approach to understand the molecular processes underlying these diseases. 32Here we apply dual RNA-seq to Orientia tsutsugamushi (Ot), an obligate intracellular bacterium and the 33 causative agent of the vector-borne human disease scrub typhus. Half the Ot genome is composed of 34 repetitive DNA, and there is minimal collinearity in gene order between strains. Integrating RNA-seq, 35 comparative genomics, proteomics, and machine learning, we investigated the transcriptional architecture 36 of Ot, including operon structure and non-coding RNAs, and found evidence for wide-spread post-37 transcriptional antisense regulation. We compared the host response to two clinical isolates and identified 38 distinct immune response networks that are up-regulated in response to each strain, leading to predictions 39 of relative virulence which were confirmed in a mouse infection model. Thus, dual RNA-seq can provide 40 insight into the biology and host-pathogen interactions of a poorly characterized and genetically 41 intractable organism such as Ot. 42 43 Keywords: neglected and emerging pathogens, intracellular bacteria, dual RNA-seq, transcriptomics, 44 host-pathogen cell biology, bacterial virulence, antisense transcription. 45 4 Main Text 46 48 serious pathogens, whilst human population growth, globalization and increased travel have contributed 49 to the emergence of new pathogens and changing patterns of infectious disease. The biology of neglected 50 and emerging pathogens is often poorly understood, but is essential to developing therapeutic and 51 preventative strategies. Obligate intracellular pathogens present additional challenges, as many cause 52 diseases that are difficult to diagnose and are difficult to manipulate experimentally. 53 54 Obligate intracellular bacteria include the Rickettsiales, an order which includes the arthropod and 55 nematode symbiont Wolbachia as well as a number of human and veterinary pathogens. Orientia 56 tsutsugamushi (Ot, Class Alphaproteobacteria, Order Rickettsiales, Family Rickettsiaceae) causes the 57 mite-borne human disease scrub typhus, a leading cause of severe febrile illness in the Asia Pacific region 1 , 58 home to roughly two thirds of the world's population. Locally acquired cases in the Middle East and Latin 59America suggest that this disease may be more widespread than previously appreciated 2,3 . Under-60 recognition and under-reporting are a major problem in scrub typhus because unambiguous diagnosis is 61 difficult, and awareness is low amongst many clinicians. Symptoms are non-specific and include 62 headache, fever, rash, and lymphadenopathy beginning 7-14 days after inoculation via a feeding larval 63 stage mite. If untreated, this can progress to cause multiple organ failure and death. In the mite vector Ot 64 colonizes...

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Section: Discussionmentioning

confidence: 99%

Dual RNA-seq provides insight into the biology of the neglected intracellular human pathogenOrientia tsutsugamushi

Mika-Gospodorz

Giengkam

Westermann

et al. 2019

Preprint

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“…Other sources of sRNAs, such as transcriptional noise and exaptation, are also considered [36]. In perspective, these authors suggest the use of molecular archeology, synthetic biology, and experimental evolution to understand better the processes underlying the generation of functional sRNAs.…”

Section: Srnas Origins and Evolutionmentioning

confidence: 99%

RNA-Sequencing Analyses of Small Bacterial RNAs and their Emergence as Virulence Factors in Host-Pathogen Interactions

Diallo

Provost

2020

IJMS

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Proteins have long been considered to be the most prominent factors regulating so-called invasive genes involved in host-pathogen interactions. The possible role of small non-coding RNAs (sRNAs), either intracellular, secreted or packaged in outer membrane vesicles (OMVs), remained unclear until recently. The advent of high-throughput RNA-sequencing (RNA-seq) techniques has accelerated sRNA discovery. RNA-seq radically changed the paradigm on bacterial virulence and pathogenicity to the point that sRNAs are emerging as an important, distinct class of virulence factors in both gram-positive and gram-negative bacteria. The potential of OMVs, as protectors and carriers of these functional, gene regulatory sRNAs between cells, has also provided an additional layer of complexity to the dynamic host-pathogen relationship. Using a non-exhaustive approach and through examples, this review aims to discuss the involvement of sRNAs, either free or loaded in OMVs, in the mechanisms of virulence and pathogenicity during bacterial infection. We provide a brief overview of sRNA origin and importance and describe the classical and more recent methods of identification that have enabled their discovery, with an emphasis on the theoretical lower limit of RNA sizes considered for RNA sequencing and bioinformatics analyses.

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“…Peptostreptococcaceae (Lawson et al, 2016). However, the evolution of sRNAs is far less understood than the evolution of proteins which can be conserved over long phylogenetic distances whereas individual sRNAs tend to display narrow conservation ranges restricted to the genus or family level (Jose et al, 2019). Interestingly, in some cases, sRNAs from distant phyla share the same function and target mRNAs despite a lack of primary sequence conservation.…”

Section: Identification Of Conserved Srna With Members Outside the CLmentioning

confidence: 99%

An RNA-centric global view ofClostridioides difficilereveals broad activity of Hfq in a clinically important Gram-positive bacterium

Fuchs

Lamm‐Schmidt

Ponath

et al. 2020

Preprint

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The Gram-positive human pathogen Clostridioides difficile has emerged as the leading cause of antibiotic-associated diarrhea. Despite growing evidence for a role of Hfq in RNA-based gene regulation in C. difficile, little is known about the bacterium′s transcriptome architecture and mechanisms of post-transcriptional control. Here, we have applied a suite of RNA-centric techniques, including transcription start site mapping, transcription termination mapping and Hfq RIP-seq, to generate a single-nucleotide resolution RNA map of C. difficile 630. Our transcriptome annotation provides information about 5′ and 3′ untranslated regions, operon structures and non-coding regulators, including 42 sRNAs. These transcriptome data are accessible via an open-access browser called ′Clost-Base′. Our results indicate functionality of many conserved riboswitches and predict novel cis-regulatory elements upstream of MDR-type ABC transporters and transcriptional regulators. Recent studies have revealed a role of sRNA-based regulation in several Gram-positive bacteria but their involvement with the RNA-binding protein Hfq remains controversial. Here, sequencing the RNA ligands of Hfq reveals in vivo association of many sRNAs along with hundreds of potential target mRNAs in C. difficile providing evidence for a global role of Hfq in post-transcriptional regulation in a Gram-positive bacterium. Through integration of Hfq-bound transcripts and computational approaches we predict regulated target mRNAs for the novel sRNA AtcS encoding several adhesins and the conserved oligopeptide transporter oppB that influences sporulation initiation in C. difficile. Overall, these findings provide a potential mechanistic explanation for increased biofilm formation and sporulation in an hfq deletion strain and lay the foundation for understanding clostridial ribo-regulation with implications for the infection process.

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Transcriptional noise and exaptation as sources for bacterial sRNAs

Cited by 28 publications

References 108 publications

Dual RNA-seq provides insight into the biology of the neglected intracellular human pathogenOrientia tsutsugamushi

Dual RNA-seq provides insight into the biology of the neglected intracellular human pathogenOrientia tsutsugamushi

RNA-Sequencing Analyses of Small Bacterial RNAs and their Emergence as Virulence Factors in Host-Pathogen Interactions

An RNA-centric global view ofClostridioides difficilereveals broad activity of Hfq in a clinically important Gram-positive bacterium

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