Anti small RNA

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Proposed mechanism for anti-sRNA relief of sRNA mediated translation inhibition. Anti-sRNA Mechanism.png
Proposed mechanism for anti-sRNA relief of sRNA mediated translation inhibition.
Antisense small RNA identification using RNA Array Antisense small RNA identification using RNA Array.jpeg
Antisense small RNA identification using RNA Array
Anti GcvB sRNA
RF02702.svg
Predicted secondary structure and sequence conservation Anti GcvB sRNA
Identifiers
Rfam RF02702
Other data
Domain(s) Bacteria
GO GO:0045975
SO SO:0000370
PDB structures PDBe
Anti stx2 sRNA
RF02703.svg
Predicted secondary structure and sequence conservation Anti stx2 sRNA
Identifiers
Rfam RF02703
Other data
Domain(s) Bacteria
GO GO:0045975
SO SO:0000370
PDB structures PDBe

Antisense small RNAs (abbreviated anti small RNA or anti-sRNA) are short RNA sequences (about 50-500 nucleotides long) that are complementary to other small RNA (sRNA) in the cell. [2]

Contents

sRNAs can repress translation via complementary base-pairing with their target mRNA sequence. [3] Anti-sRNAs function by complementary pairing with sRNAs before the mRNA can be bound, thus freeing the mRNA and relieving translation inhibition. [4] Anti-sRNAs lead to higher expression of mRNAs by inhibiting the action of sRNAs. [1] Sponge RNA is another term used to describe anti-sRNAs. [5]

Discovery and Identification Methods

While the mRNA-regulating small RNAs were discovered in 1984, the first natural anti-sRNA was only discovered in 2014 in an Escherichia coli model. [1] [6] The initial characterization of antisense small RNA within E. coli models were demonstrated through microarrays and computational predictions. [7] Recent experiments have used Northern blot analysis and 5'-end mapping to correctly identify potential antisense sRNA candidates. [8] RNA-Seq has emerged as a popular method for the identification of small RNA, since its ability to distinguish between messenger and structural RNA allows for increased sensitivity in sRNA analysis. [9] [10] Strand-specific RNA-Seq provides further characterization of sRNA by predicting transcript structures with enhanced accuracy. [9] [11] In 2019, a new algorithm called APERO was established which allows accurate genome-wide detection of small transcripts from paired-end bacterial RNA-Seq data. [10] Paired-end bacterial sequencing allows for sequencing across both ends of the fragment, which increases the accuracy of the read by providing enhanced alignment. [12]

Protein-binding oriented techniques such as cross-linking immunoprecipitation, which isolates anti-sRNAs bound to proteins, have further contributed to the identification and detection of new anti-sRNA. A major contributor to this approach is the Hfq protein, a conserved RNA-binding protein that is known to attach various sRNAs. [13] However, cross-linking immunoprecipitation fails to provide information on which two RNAs are interacting with each other, which is critical to identify the regulatory role of sRNAs. This shortcoming has been remedied by utilizing an RNA ligase to join the ends of the two RNAs that are interacting, allowing the mapping of sRNAs that are interacting with each other using RNA-Seq. [5]

Function

Antisense small RNA are found in all domains of life, including Eukaryotes, Bacteria and Archaea. [14] [15] They are non-coding RNA sequences involved in regulatory processes, such as metabolism and aiding in transcription. [14] Many anti-sRNAs are involved in regulatory activities to modulate gene expression, with the bulk of research exploring specific interactions within the bacterial domain. [16] [17] One example of this is established in bacterial trans-encoded sRNA, which demonstrate only partial complementarity to the target RNA. [18] These sRNA function to modulate base-pair interactions and translation by directly targeting the mRNA, thereby affecting its stability. [19] Anti-sRNAs are able to interact with other sRNAs by targeting either the region involved in targeting the mRNA, or it can bind to another corresponding region along the sRNA. [7] This has further been characterized in gene circuits that are sRNA-controlled and regulate aspects of bacterial pathogenesis. [19]

Antisense small RNA can also be engineered and utilized by scientists to perform experimental functions. [20] In synthetic biology, employing non-coding RNA such as antisense small RNA has advantages for creating regulatory architecture within engineering systems, provided the ability to predict function using the strand sequence. [20] In experiments, engineered riboregulators, which are specific RNA that respond to signal RNA through complementary base pairing utilizing anti-small RNA, have been found to be capable of activating independent gene expression. [20] Development of RNA array-based interaction assays that allow for screening in vitro have further advanced platforms targeting gene expression with antisense small RNAs. [19] [21] RNA-array based interaction assays screen for synthetic antisense small RNA interactions in vitro, through a surface-capture technique. [19] [21] An array of immobilized double-stranded DNA template for antisense small RNA sits opposite to an RNA-capture surface composed of possible antisense small RNA targets, separated by a solution of transcription reagents. [19] [21] Captured RNA are visualized using fluorescent staining, which can indicate whether a prospective antisense small RNA has been bound to its target. [19] [21]

Anti-bacterial targeting of V. cholerae occurs through the promotion of gene expression patterns that liberate bacteria from its host. [19] [21] This has been achieved by utilizing antisense small RNAs designed through the RNA array pipeline, opening the possibilities for future antimicrobial or therapeutic applications. [19] [21]

Examples

AsxR

AsxR, previously known as EcOnc02, is an anti-sRNA encoded within the 3' region of the stx2B gene of E.Coli bacteria. [1] It acts to increase expression of the ChuS heme oxygenase via destabilisation of FnrS sRNA. [1] This aids bacterial infection of the animal host gut. [1]

AgvB

AgvB, previously known as EcOnc01, inhibits GcvB sRNA repression. [1] Pathogenicity island associated AgvB aids enterohemorrhagic E. coli growth at the colonized site within the host animal. [1] This bacterial growth often manifests into an increased risk of developing other conditions such as hemolytic uremic syndrome.

RosA

RosA, has been found to inhibit two sRNAs (RoxS and FsrA). [22] Inhibition of RoxS by RosA plays a role in metabolism regulation, while FsrA is involved in maintaining iron availability for protein function. [22] RosA is also the first antisense small RNA experimentally confirmed in Gram-positive bacteria. [22]

Related Research Articles

The gene rpoS encodes the sigma factor sigma-38, a 37.8 kD protein in Escherichia coli. Sigma factors are proteins that regulate transcription in bacteria. Sigma factors can be activated in response to different environmental conditions. rpoS is transcribed in late exponential phase, and RpoS is the primary regulator of stationary phase genes. RpoS is a central regulator of the general stress response and operates in both a retroactive and a proactive manner: it not only allows the cell to survive environmental challenges, but it also prepares the cell for subsequent stresses (cross-protection). The transcriptional regulator CsgD is central to biofilm formation, controlling the expression of the curli structural and export proteins, and the diguanylate cyclase, adrA, which indirectly activates cellulose production. The rpoS gene most likely originated in the gammaproteobacteria.

<span class="mw-page-title-main">DicF RNA</span> Non-coding RNA

DicF RNA is a non-coding RNA that is an antisense inhibitor of cell division gene ftsZ. DicF is bound by the Hfq protein which enhances its interaction with its targets. Pathogenic E. coli strains possess multiple copies of sRNA DicF in their genomes, while non-pathogenic strains do not. DicF and Hfq are both necessary to reduce FtsZ protein levels, leading to cell filamentation under anaerobic conditions.

<span class="mw-page-title-main">DsrA RNA</span> Non-coding RNA

DsrA RNA is a non-coding RNA that regulates both transcription, by overcoming transcriptional silencing by the nucleoid-associated H-NS protein, and translation, by promoting efficient translation of the stress sigma factor, RpoS. These two activities of DsrA can be separated by mutation: the first of three stem-loops of the 85 nucleotide RNA is necessary for RpoS translation but not for anti-H-NS action, while the second stem-loop is essential for antisilencing and less critical for RpoS translation. The third stem-loop, which behaves as a transcription terminator, can be substituted by the trp transcription terminator without loss of either DsrA function. The sequence of the first stem-loop of DsrA is complementary with the upstream leader portion of RpoS messenger RNA, suggesting that pairing of DsrA with the RpoS message might be important for translational regulation. The structures of DsrA and DsrA/rpoS complex were studied by NMR. The study concluded that the sRNA contains a dynamic conformational equilibrium for its second stem–loop which might be an important mechanism for DsrA to regulate the translations of its multiple target mRNAs.

<span class="mw-page-title-main">GcvB RNA</span>

The gcvB RNA gene encodes a small non-coding RNA involved in the regulation of a number of amino acid transport systems as well as amino acid biosynthetic genes. The GcvB gene is found in enteric bacteria such as Escherichia coli. GcvB regulates genes by acting as an antisense binding partner of the mRNAs for each regulated gene. This binding is dependent on binding to a protein called Hfq. Transcription of the GcvB RNA is activated by the adjacent GcvA gene and repressed by the GcvR gene. A deletion of GcvB RNA from Y. pestis changed colony shape as well as reducing growth. It has been shown by gene deletion that GcvB is a regulator of acid resistance in E. coli. GcvB enhances the ability of the bacterium to survive low pH by upregulating the levels of the alternate sigma factor RpoS. A polymeric form of GcvB has recently been identified. Interaction of GcvB with small RNA SroC triggers the degradation of GcvB by RNase E, lifting the GcvB-mediated mRNA repression of its target genes.

<span class="mw-page-title-main">OmrA-B RNA</span>

The OmrA-B RNA gene family is a pair of homologous OmpR-regulated small non-coding RNA that was discovered in E. coli during two large-scale screens. OmrA-B is highly abundant in stationary phase, but low levels could be detected in exponentially growing cells as well. RygB is adjacent to RygA a closely related RNA. These RNAs bind to the Hfq protein and regulate gene expression by antisense binding. They negatively regulate the expression of several genes encoding outer membrane proteins, including cirA, CsgD, fecA, fepA and ompT by binding in the vicinity of the Shine-Dalgarno sequence, suggesting the control of these targets is dependent on Hfq protein and RNase E. Taken together, these data suggest that OmrA-B participates in the regulation of outer membrane composition, responding to environmental conditions.

<span class="mw-page-title-main">MicC RNA</span>

The MicC non-coding RNA is located between the ompN and ydbK genes in E. coli. This Hfq-associated RNA is thought to be a regulator of the expression level of the OmpC porin protein, with a 5′ region of 22 nucleotides potentially forming an antisense interaction with the ompC mRNA. Along with MicF RNA this family may act in conjunction with EnvZ-OmpR two-component system to control the OmpF/OmpC protein ratio in response to a variety of environmental stimuli. The expression of micC was shown to be increased in the presence of beta-lactam antibiotics.

<span class="mw-page-title-main">OxyS RNA</span>

OxyS RNA is a small non-coding RNA which is induced in response to oxidative stress in Escherichia coli. This RNA acts as a global regulator to activate or repress the expression of as many as 40 genes, by an antisense mechanism, including the fhlA-encoded transcriptional activator and the rpoS-encoded sigma(s) subunit of RNA polymerase. OxyS is bound by the Hfq protein, that increases the OxyS RNA interaction with its target messages. Binding to Hfq alters the conformation of OxyS. The 109 nucleotide RNA is thought to be composed of three stem-loops.

<span class="mw-page-title-main">Sib RNA</span>

Sib RNA refers to a group of related non-coding RNA. They were originally named QUAD RNA after they were discovered as four repeat elements in Escherichia coli intergenic regions. The family was later renamed Sib when it was discovered that the number of repeats is variable in other species and in other E. coli strains.

<span class="mw-page-title-main">RyhB</span> 90 nucleotide RNA

RyhB RNA is a 90 nucleotide RNA that down-regulates a set of iron-storage and iron-using proteins when iron is limiting; it is itself negatively regulated by the ferric uptake repressor protein, Fur.

<span class="mw-page-title-main">MicA RNA</span>

The MicA RNA is a small non-coding RNA that was discovered in E. coli during a large scale screen. Expression of SraD is highly abundant in stationary phase, but low levels could be detected in exponentially growing cells as well.

<span class="mw-page-title-main">ArcZ RNA</span>

In molecular biology the ArcZ RNA is a small non-coding RNA (ncRNA). It is the functional product of a gene which is not translated into protein. ArcZ is an Hfq binding RNA that functions as an antisense regulator of a number of protein coding genes.

<span class="mw-page-title-main">SroB RNA</span>

The sroB RNA is a non-coding RNA gene of 90 nucleotides in length. sroB is found in several Enterobacterial species but its function is unknown. SroB is found in the intergenic region on the opposite strand to the ybaK and ybaP genes. SroB is expressed in stationary phase. Experiments have shown that SroB is a Hfq binding sRNA.

<span class="mw-page-title-main">Hfq protein</span>

The Hfq protein encoded by the hfq gene was discovered in 1968 as an Escherichia coli host factor that was essential for replication of the bacteriophage Qβ. It is now clear that Hfq is an abundant bacterial RNA binding protein which has many important physiological roles that are usually mediated by interacting with Hfq binding sRNA.

c4 antisense RNA

The c4 antisense RNA is a non-coding RNA used by certain phages that infect bacteria. It was initially identified in the P1 and P7 phages of E. coli. The identification of c4 antisense RNAs solved the mystery of the mechanism for regulation of the ant gene, which is an anti-repressor.

<span class="mw-page-title-main">MicX sRNA</span>

MicX sRNA is a small non-coding RNA found in Vibrio cholerae. It was given the name MicX as it has a similar function to MicA, MicC and MicF in E. coli. MicX sRNA negatively regulates an outer membrane protein and also a component of an ABC transporter. These interactions were predicted and then confirmed using a DNA microarray.

Bacterial small RNAs (bsRNA) are small RNAs produced by bacteria; they are 50- to 500-nucleotide non-coding RNA molecules, highly structured and containing several stem-loops. Numerous sRNAs have been identified using both computational analysis and laboratory-based techniques such as Northern blotting, microarrays and RNA-Seq in a number of bacterial species including Escherichia coli, the model pathogen Salmonella, the nitrogen-fixing alphaproteobacterium Sinorhizobium meliloti, marine cyanobacteria, Francisella tularensis, Streptococcus pyogenes, the pathogen Staphylococcus aureus, and the plant pathogen Xanthomonas oryzae pathovar oryzae. Bacterial sRNAs affect how genes are expressed within bacterial cells via interaction with mRNA or protein, and thus can affect a variety of bacterial functions like metabolism, virulence, environmental stress response, and structure.

<i>Escherichia coli</i> sRNA

Escherichia coli contains a number of small RNAs located in intergenic regions of its genome. The presence of at least 55 of these has been verified experimentally. 275 potential sRNA-encoding loci were identified computationally using the QRNA program. These loci will include false positives, so the number of sRNA genes in E. coli is likely to be less than 275. A computational screen based on promoter sequences recognised by the sigma factor sigma 70 and on Rho-independent terminators predicted 24 putative sRNA genes, 14 of these were verified experimentally by northern blotting. The experimentally verified sRNAs included the well characterised sRNAs RprA and RyhB. Many of the sRNAs identified in this screen, including RprA, RyhB, SraB and SraL, are only expressed in the stationary phase of bacterial cell growth. A screen for sRNA genes based on homology to Salmonella and Klebsiella identified 59 candidate sRNA genes. From this set of candidate genes, microarray analysis and northern blotting confirmed the existence of 17 previously undescribed sRNAs, many of which bind to the chaperone protein Hfq and regulate the translation of RpoS. UptR sRNA transcribed from the uptR gene is implicated in suppressing extracytoplasmic toxicity by reducing the amount of membrane-bound toxic hybrid protein.

<span class="mw-page-title-main">CRISPR interference</span> Genetic perturbation technique

CRISPR interference (CRISPRi) is a genetic perturbation technique that allows for sequence-specific repression of gene expression in prokaryotic and eukaryotic cells. It was first developed by Stanley Qi and colleagues in the laboratories of Wendell Lim, Adam Arkin, Jonathan Weissman, and Jennifer Doudna. Sequence-specific activation of gene expression refers to CRISPR activation (CRISPRa).

Bacterial small RNAs (sRNA) are an important class of regulatory molecules in bacteria such as Brucella. They are often bound to the chaperone protein Hfq, which allows them to interact with mRNA(s). In Brucella suis 1330 RNA sequencing identified a novel list of 33 sRNAs and 62 Hfq-associated mRNAs. In Brucella melitensis eight novel sRNA genes were identified using bioinformatic and experimental approach. One of them BSR0602 was found to modulate the intracellular survival of B. melitensis. In another large-scale deep sequencing study 1321 sRNAs were identified in B. melitensis. BSR0441 sRNA was further investigated in this study and shown to play role in the intracellular survival. sRNA BM-sr0117 from Brucella melitensis was identified and shown to be bound to and cleaved by Bm-RNase III. AbcR and AbcR2 were studied B. abortus. Seven novel sRNAs were validated and their interaction with a putative target sequence was verified in B. abortus.

References

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