[RNA Biology 4:3, e1-e1, EPUB Ahead of Print: http://www.landesbioscience.com/journals/rnabiology/article/5308; July–December 2007]; ©2007 Landes Bioscience
Meeting Report
Sensory and Regulatory RNAs in Prokaryotes:
A New German Research Focus
Franz Narberhaus1,*
Jörg Vogel2
A priority program on regulatory RNAs in prokaryotes
This manuscript has been published online, prior to printing for RNA Biology, Volume
4, Issue 3. Definitive page numbers have not been assigned. The current citation is:
RNA Biology 2007; 4(3):
http://www.landesbioscience.com/journals/rnabiology/article/5308
Once the issue is complete and page numbers have been assigned, the citation
will change accordingly.
Key words
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Riboswitch, small RNA, regulatory RNA,
noncoding RNA, Hfq
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Original manuscript submitted: 11/10/07
Manuscript accepted:11/16/07
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*Correspondence to: Franz Narberhaus; Ruhr-Universität Bochum; Lehrstuhl für
Biologie der Mikroorganismen; NDEF 06/783; Universitätsstrasse 150; Bochum
D-44780 Germany; Tel.: +49.234.322.3100; Fax: +49.234.321.4620;
Email: [email protected]
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2RNA Biology; Max-Planck Institute for Infection Biology; Berlin, Germany
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1Microbial Biology; Ruhr-University; Bochum, Germany
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The fundamental role of regulatory RNAs in controlling gene expression in eukaryotes
and prokaryotes is receiving ever growing attention. The German Research Foundation
(DFG) has recognized the importance of this field, and will support a special research
program on Sensory and regulatory RNAs in prokaryotes for six years. The program is
being coordinated by Franz Narberhaus (Ruhr University Bochum) with help from Jörg
Vogel (Max Planck Institute for Infection Biology, Berlin), Gabriele Klug (University
of Giessen) and Robert Giegerich (University of Bielefeld). Following evaluation of
38 research proposals by an international panel of expert scientists in January 2007, the
DFG decided to allocate funding for an initial period of three years (starting April 2007)
to a total of 23 groups from all over the German map from Kiel to Freiburg and from
Bochum to Greifswald.
Generally speaking, the intention of DFG priority programs is to support “emerging
fields.” The aim of the program featured here is to bring together scientists to explore
the regulatory potential of RNA in diverse prokaryotic systems. That is apart from the
standard model bacteria, Escherichia coli and Bacillus subtilis, several other microbes
including cyanobacteria, Rhizobiaceae, several pathogens, and halophilic as well as
methanogenic archaea will be studied. Recent bioinformatics aided and experimental
approaches have revealed a large number of potential cis and trans acting riboregulators
in any given organism.1,2 However, except for a few selected examples, the contribution
of all these regulatory RNAs to cellular physiology remains elusive, in particular if non
standard model organisms are concerned. Scientists from various disciplines (genetics,
microbiology, bioinformatics, biochemistry, chemistry and structural biology) have joint
forces to travel this unpaved road. Several projects currently are in an initial data mining
phase. To facilitate the identification of novel RNA regulators, funding by the DFG
includes (limited) support for joint resources such as tiling arrays and massively parallel
pyrosequencing (454) reactions. Once promising RNAs have been selected, they will be
subjected to detailed structure function studies.
Annual meetings are an important platform to facilitate communication between
the participating research groups. A kick off meeting was hosted by the Ruhr University
Bochum on September 5th and 6th, 2007. Twenty talks covering nearly all of the funded
projects, and supplementary poster sessions, provided an excellent opportunity for 70
participants to discuss recent data and to establish new collaborations in a very stimulating
environment.
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Acknowledgements
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We are grateful to the German Research
Foundation for financial support of the
meeting (DFG NA 240/6-1).
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cis acting RNAs
Most bacterial mRNAs contain a 5' untranslated region (5' UTR) with more than the
Shine Dalgarno (SD) sequence required for interaction with the 30S ribosomal particle.
Such extended 5' UTRs can fold into complex structures with regulatory properties. RNA
thermometers, for example, acquire a structure that blocks translation at low temperatures.
A temperature upshift induces melting of the hairpin structure, thus liberating the SD
sequence. Franz Narberhaus reported on two classes of RNA thermometers that differ
in their sequence and structure. ROSE (Repression Of heat Shock gene Expression) like
elements control the expression of small heat shock genes in many α and γ proteobacteria and are characterized by a short consensus sequence that loosely pairs with the SD
sequence.3 A NMR study revealed a temperature-labile network of non-canonical base
pairs in the region where melting of the RNA initiates.4 FourU type RNA thermometers
are predicted to occur upstream of various bacterial heat shock and virulence genes.
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Sensory and Regulatory RNAs in Prokaryotes
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Participants of the kick off meeting with Franz Narberhaus (left) and Jörg Vogel (right) in front.
In close collaboration with Beatrix Suess (University of Frankfurt),
Oliver Weichenrieder carried out a detailed thermodynamic analysis
of an engineered tetracycline binding riboswitch. Using fluorimetry,
they determined a dissociation constant for tetracycline of 700 pM;
the highest affinity reported so far for a small molecule binding RNA
aptamer.10 Progress towards the crystal structure of this complex was
presented.
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As the name indicates, they make use of four uridine residues that
block the SD sequence at low temperature.5 New candidates of both
classes of RNA thermometers are currently being studied.
Riboswitches control gene expression by ligand induced conformational changes that control transcription termination, translation
initiation or RNA processing.2 The Schwalbe group (University
of Frankfurt) has investigated the structure and folding of purine
sensing riboswitches in their apo state, in the ligand bound state,6,7
and also the structural transition between those two states by time
resolved NMR.8 The free form of the guanine and adenine sensing
riboswitches differ in their pre-organization of the loop-loop interaction, which can be attributed to a single base pair difference in the
two riboswitches. Hypoxanthine induced folding of the aptamer
domain of the guanine riboswitch from the xpt pbuX operon of
B. subtilis was monitored at atomic resolution.8 Three distinct
kinetic steps for the ligand induced folding could be dissected.
Following initial complex encounter the ligand binding pocket is
formed resulting in the subsequent stabilization of a remote long
range loop loop interaction. RNA folding proceeds from an apo-state
with loosely defined interhelical angles through a dynamic intermediate with native state like yet dynamic helix helix orientation.
Artificial, engineered riboswitches were introduced by Sabine
Müller (University of Greifswald) and Oliver Weichenrieder (Max
Planck Institute for Developmental Biology, Tübingen). Sabine
Müller’s lab has developed a hairpin aptazyme that responds to flavine
mononucleotide (FMN). Ribozyme activity is switched on in the
presence of FMN in the oxidized state. Under reducing conditions,
FMN changes its molecular geometry, which is associated with loss
of binding and consequently downregulation of ribozyme activity.
The established principle of FMN induced switching between two
alternative RNA conformations allows studying the folding and
refolding of the natural FMN riboswitch in a reversible manner.9
www.landesbioscience.com
trans acting RNAs
A total of 16 presentations in four sessions reflected the central
role of small noncoding regulatory RNAs (sRNAs) in the priority
program. Recent estimates suggest that a typical microbial genome
may encode hundreds of regulatory RNAs.11 Such sRNAs are
generally untranslated, and most often range from 50–250 nucleotides in length. Where characterized in detail, some sRNAs were
found to regulate target genes by binding to (regulatory) proteins,
whilst most of them turned out as antisense RNAs that act on
trans-encoded mRNAs. Unlike the cis encoded antisense RNAs of
plasmids, transposons and phages,12 trans encoded antisense RNAs
typically have only short and imperfect complementarity with their
targets. One frequently observed mechanism involves competition
between antisense RNAs and initiating ribosomes, resulting in
translational inhibition. However, bacterial sRNAs have also been
reported as post transcriptional, translational activators of mRNAs.
Such sRNAs typically base pair to an mRNA leader segment that
normally sequesters a ribosome binding site; as a result the otherwise
poorly translated mRNA becomes translationally active.13
Enterobacteria have been the traditional workhorses for bacterial
sRNA research, and much of the currently available information
regarding sRNA numbers and mechanisms stem from these species.
Jörg Vogel started with a brief overview of sRNAs in Escherichia coli
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environmental control of physiological processes and virulence
factors, which are crucial for the initiation of Yersinia infection.
Two projects aim at the identification of small RNAs in α
proteobacteria. Anke Becker (University of Bielefeld) showed how
closely related Rhizobiales genomes were queried for computational
predictions of sRNA genes, with a focus on Sinorhizobium meliloti
as a model organism for experimental identification of these RNAs.
Fractionation of RNA and expression profiling in a broad range of
growth conditions resulted in the identification of a considerable
number of candidates that now have to be validated experimentally.
Bioinformatics tools for characterization of RNAs and for speeding
up database searches are being developed in close collaboration with
Robert Giegerich.23,24
In a similar approach, candidates for non coding RNAs in
S. meliloti were predicted by comparative genomics25 based on the
published genome sequences of S. meliloti, Agrobacterium tumefaciens
and Bartonella henselae. Elena Evguenieva Hackenberg (University
of Giessen) verified three of the predicted RNAs experimentally:
the highly conserved signal recognition particle (SRP) RNA and
two small RNAs of unknown function with approximate lengths of
110 and 80 nucleotides, respectively. Both RNAs are differently
expressed at different growth stages and in different growth media.
The physiological role of these novel RNAs is under investigation.
The detection of new functional RNAs requires new comparative methods for motif detection since the RNA sequence is much
less conserved than the RNA structure. The ‘gold standard’ for
sequence structure alignment are Sankoff like approaches, which
perform simultaneous alignment and folding, but usually require
extreme amounts of memory and space. Rolf Backofen (University
of Freiburg) presented the new Sankoff like approach LocaRNA,
which is much more efficient than previous approaches and thus can
be used on a genomic scale.26 Second, he presented the MEMERIS
approach, which allows finding protein binding sites in RNA (such
as splice enhancer/silencer or Hfq binding sites). Here, one searches
not for a sequence/structure motif, but for common sequence motifs
that share structural properties like being single stranded.27
The Stadler group presented three computer programs to predict
and verify non coding RNAs. The first one is NcDNAlign28 which
generates multiple sequence alignments (MSA) of non protein
coding genomic sequences in an efficient and customizable way.
This program is based on a pipeline concept which combines
custom written and standard bioinformatic (e.g. BLAST) software
tools. Structured ncRNAs (tRNA, rRNA, ...) have a defined and
evolutionary conserved secondary structure which is of functional
importance. To predict such ncRNAs for a species of interest
given MSA the program RNAz29 could be used. Computationally
predicted RNA families can be grouped together, forming a ncRNA
class whose members have no discernible homology at sequence
level, but still share common structural and functional properties by
applying the LocARNA based clustering approach.26
Cyanobacteria were in the focus of yet another session of oral
presentations. Wolfgang Hess and his group (University of Freiburg)
are working on the identification and functional annotation of non
coding RNAs in the model cyanobacterium Synechocystis PCC6803
and the marine cyanobacterium Synechococcus WH 7803 by either
linking an effective scoring of multiple alignments in terms of
secondary structure conservation to comparative genomics25 or by a
combination of a promoter structural search with certain motifs that
occur in non-coding RNA30 accompanied by RNomics, microarray
and manual verification experiments. The prediction methods have
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and Salmonella, followed by the introduction into a GFP based
reporter system that has proven a valuable tool for their in vivo studies
of target mRNA regulation by a diverse set of sRNAs.14 Members of
his group also presented posters on two well conserved sRNAs known
or predicted to directly interact with a large set of target mRNAs.
These are the 200 nt GcvB RNA which was recently demonstrated to
control the translation of at least seven ABC transporter mRNAs,15
and the 90 nt RybB RNA that facilitates global mRNA repression
within the σE controlled envelope stress response.16
Two presentations were devoted to the structure and function
of bacterial 6S RNA, which is a ubiquitous small bacterial sRNA
that has only recently been found to function as a growth phase
dependent riboregulator of transcription.17 E. coli 6S RNA has
been shown to form stable complexes with the sigma70 RNA polymerase holoenzyme and serves as a template for the synthesis of
RNA oligonucleotides during outgrowth from stationary phase.18
The goal of Rolf Wagner’s project (University of Düsseldorf )
is to better understand the mechanism(s) by which 6S RNA
regulates the change in transcriptional specificity when bacteria enter
changing growth conditions. Studies involve the molecular analysis
of global and specific transcription processes in vitro and in vivo.
Elucidation of the role of different sigma factors in 6S RNA mediated
transcriptional control as well as the characterization of the hitherto
unknown promoter specificities are further important milestones of
the project. The studies include a detailed analysis of how 6S RNA
itself is regulated and linked to the network of stress and growth
phase adaptation.19
In contrast to E. coli with only one 6S RNA gene, the B. subtilis
genome harbors two 6S RNA homologs, termed bsrA and bsrB.
Roland Hartmann and Dagmar Willkomm (University of Marburg)
reported on the construction and characterization of individual
and combined knockouts of both 6S RNA genes in different strain
backgrounds. Intriguingly, increased bacterial lysis was observed with
the double knockout strain in stationary phase, further arguing that
6S RNA is an important regulator in dormant bacteria.
The role of RNA processing for the function of E. coli sRNAs is
being investigated by the group of Gabriele Klug. In focus are those
sRNAs affecting rpoS expression, which will be studied in collaboration with Regine Hengge (Free University, Berlin). The turnover of
rpoS mRNA is independent of growth phase but depends on the
presence of Hfq and the small RNA, OxyS.20 OxyS processing was
observed to be growth phase dependent, and it will be interesting
to see if these growth effects are related to the availability of OxyS
target mRNAs.
Several presentations dealt with the potential roles of sRNAs in
host microbe interactions. Here, the groups of Ulla Bonas (University
of Halle) and Peter Stadler (University of Leipzig) have initiated a
project to characterize sRNAs in the plant pathogen Xanthomonas
campestris. Initial results of this screen were presented. Petra Dersch
(University of Braunschweig) presented that the global MarR type
transcription activator RovA of Yersinia pseudotuberculosis virulence
and stress adaptation genes is controlled by a Csr type regulatory
system, which implicates at least two different small regulatory
RNAs.21 The two identified Csr type RNAs were shown to activate
rovA transcription in response to the nutrient composition of the
medium by regulating the synthesis of the LysR type regulator RovM,
which inhibits the expression of the rovA gene.22 The Yersinia Csr
type system was also found to have a major effect on the overall
fitness, carbon metabolism and motility of the bacteria, indicating
that the Csr type regulatory RNAs are key components in the
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Very little is known about the function of small RNAs in
archaea, and much of the RNA research in this kingdom of life has
so far focused on the identification of snoRNAs (small nucleolar
RNAs) which guide ribosomal RNA modification.39,40 To which
extent these organisms express other noncoding RNAs has been
largely unknown. Two archaeal species with very interesting physiology, namely methanogenic Methanosarcina mazei and halophilic
Haloferax volcanii, will be scrutinized to identify new sRNA species.
The lab of Ruth Schmitz-Streit (University of Kiel), in collaboration with partners Hess and Liesegang (University of Göttingen),
has embarked on a genome wide sRNA screen using comparative
analyses of the three Methanosarcina genomes (M. mazei, M. barkeri,
M. acetivorans). Their preliminary results predicted more than 600
potential sRNAs to be encoded by the ~4 Mb genome of M. mazei.
Validation of these sRNAs will focus on those candidate genes that
are situated in vicinity of genes involved in nitrogen stress response.41
The expression of two of the predicted sRNAs, which are encoded
adjacent to transcriptional regulators, has already been verified by
quantitative RT PCR and Northern blot analysis. Anita Marchfelder
(University of Ulm) and Jörg Soppa (University of Frankfurt) have
combined experimental RNomics42 and bioinformatics aided predictions43 to identify the sRNAs of H. volcanii. To characterize their
biological role, deletion mutants of a number of these candidates are
being constructed and characterized. H. volcanii also encodes a Sm
like protein similar to Hfq, and it is planned to clone sRNAs that co
immunoprecipitate with this protein. Surprisingly, H. volcanii seems
to be the first organism in which an Hfq like protein appears to be
essential since various attempts to delete this gene have so far been
unsuccessful.
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proven potential to be applied on other bacteria as well.31 In order
to reveal functions of regulatory RNAs that depend on the RNA
chaperone Hfq in Synechocystis sp. PCC 6803, Annegret Wilde
(Humboldt University Berlin) has constructed mutants lacking
or overexpressing Hfq. She showed the specific function of the
Synechocystis Hfq in motility and type IV pili formation.
Claudia Steglich (University of Freiburg) reported on an integrative approach that takes advantage of the availability of high density
microarray expression data for the cyanobacterium, Prochlorococcus
MED4.32 This fascinating marine model organism is also attractive
to study in terms of sRNAs because it lacks Hfq and possesses a very
compact genome (1.7 Mbp). In addition to the previously known
ten Prochlorococcus sRNAs,25 tiling array analysis helped identify
11 new sRNAs in this organism. Furthermore, the data suggests the
existence of more than 100 small protein coding open reading frames
currently not annotated in the published genome sequence, as well as
the presence of a significant number of cis encoded antisense RNAs.
Small RNAs in Gram positive bacteria and archaea were the topic
in the final session. Sabine Brantl and co workers (University of Jena)
recently identified two small RNAs—SR1 and SR2—in intergenic
regions of the B. subtilis genome using a computational approach.
The 205 nucleotides long SR1 RNA has already been characterized
in some detail and a first primary target, ahrC mRNA, has been
identified.33,34,35 The 115 nucleotides long SR2 RNA is not essential in B. subtilis. Expression profiling indicates that SR2 is expressed
constitutively in complex and minimal medium with a peak in
logarithmic growth phase. Preliminary microarray analyses with total
RNA from wild type and knockout strains suggest that SR2 has at
least three targets.
Jörg Stülke (University of Göttingen) presented data on the interaction between the B. subtilis CsrA protein and the non coding RsmY
RNA in vitro. To provide further evidence for this interaction and in
order to identify other potential partners of CsrA, the group intends
to co purify these RNAs with CsrA from B. subtilis using the SPINE
technology.36 The analysis of a csrA mutant revealed that CsrA is
essential for motility in B. subtilis.
Roland Brückner (University of Kaiserslautern) presented five
small RNAs from Streptococcus pneumoniae, which belong to the
regulon of the two component regulatory system CiaRH.37 These
sRNAs, which were baptized the “csRNAs,” come in sizes between
90 and 150 nucleotides, and show a high degree of similarity to one
another. Studies with S. pneumoniae strains lacking individual or
several csRNAs indicated that csRNA4 and csRNA5 are involved
in the control of stationary phase autolysis and perhaps competence
development.
Of the many fascinating model bacteria studied within the
network, Streptomyces coelicolor is a member of the group of Gram
positive filamentous soil dwelling bacteria with a high G+C content.
It undergoes a complex morphogenesis and produces a variety of
antibiotics and bioactive secondary metabolites. The group of Beatrix
Suess (University of Frankfurt a.M.) took a bioinformatics driven
approach to predict sRNAs in this organism, with a particular focus
on sRNAs whose expression could be controlled by DasR, a global
regulator in streptomycetes involved in development and basal
metabolism.38 DasR control of the expression of one of the predicted
candidates, baptized sc1, has been confirmed. Another candidate
sRNA locus, sc32, was found to be expressed specifically upon cold
shock. The characterization of targets and regulatory mechanisms of
these sRNAs will no doubt give new insight into how specificity of
base pairing is achieved by G/C rich RNAs.
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Perspectives
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RNA mediated regulation in prokaryotes has become a very
timely topic. The data presented at this conference left no doubt that
regulatory RNAs profoundly impact on the physiology of eubacteria
and archaea. Owing to the only recent establishment of the DFG
priority program, most participating groups are at current still in the
early stages of their projects. Nonetheless, the oral presentations and
the lively posters sessions promised fascinating results in the more
than five years ahead of us. The fact that more than 20 groups have
teamed up to work in a competitive research area leads us to expect
extensive collaborations. Biocomputational pipelines will reveal
novel regulatory RNAs and potential targets. Microbiologists and
biochemists will aim at uncovering physiological roles and regulatory
mechanisms of these new RNAs, which will then be followed up by
structural biologists to link function to molecular structure. In fact,
multiple collaborations have already been established following the
first roundtable discussions in September 2005 which eventually
led to the launch of this priority program. Moreover, the first joint
publications from members of the network tell that this interdisciplinary concept might work, indeed.5,10,44
The recent kick off meeting will soon be followed by another
internal meeting (September 2008). In addition, an international
conference on Sensory and Regulatory RNAs in Prokaryotes has been
scheduled to take place in Berlin June 3–6, 2009. We hope that this
event will bring together the ever growing community of those who
are fascinated with prokaryotic riboregulators.
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31. Chen XH, Koumoutsi A, Scholz R, Eisenreich A, Schneider K, Heinemeyer I, Morgenstern
B, Voss B, Hess WR, Reva O, Junge H, Voigt B, Jungblut PR, Vater J, Süssmuth R,
Liesegang H, Strittmatter A, Gottschalk G, Borriss R. Comparative analysis of the complete genome sequence of the plant growth promoting bacterium Bacillus amyloliquefaciens
FZB42. Nat Biotechnol 2007; 25:1007-14.
32. Steglich C, Futschik M, Rector T, Steen R, Chisholm SW. Genome wide analysis of light
sensing in Prochlorococcus. J Bacteriol 2006; 188:7796-806.
33. Heidrich N, Moll I, Brantl S. In vitro analysis of the interaction between the small RNA
SR1 and its primary target ahrC mRNA. Nucleic Acids Res 2007; 35:4331-46.
34. Heidrich N, Chinali A, Gerth U, Brantl S. The small untranslated RNA SR1 from the
Bacillus subtilis genome is involved in the regulation of arginine catabolism. Mol Microbiol
2006; 62:520-36.
35. Licht A, Preis S, Brantl S. Implication of CcpN in the regulation of a novel untranslated
RNA (SR1) in Bacillus subtilis. Mol Microbiol 2005; 58:189-206.
36. Herzberg C, Flórez Weidinger LA, Dörrbecker B, Hübner S, Stülke J, Commichau FM.
SPINE: A method for the rapid detection and analysis of protein protein interactions in
vivo. Proteomics 2007; 7:4032-5.
37. Halfmann A, Kovacs M, Hakenbeck R, Brückner R. Identification of the genes directly controlled by the response regulator CiaR in Streptococcus pneumoniae: five out of 15 promoters
drive expression of small non coding RNAs. Mol Microbiol 2007; 66:110-26.
38. Rigali S, Nothaft H, Noens EE, Schlicht M, Colson S, Müller M, Joris B, Koerten HK,
Hopwood DA, Titgemeyer F, van Wezel GP. The sugar phosphotransferase system of
Streptomyces coelicolor is regulated by the GntR family regulator DasR and links N acetylglucosamine metabolism to the control of development. Mol Microbiol 2006; 61:1237-51.
39. Tang TH, Bachellerie JP, Rozhdestvensky T, Bortolin ML, Huber H, Drungowski M, Elge
T, Brosius J, Hüttenhofer A. Identification of 86 candidates for small non messenger RNAs
from the archaeon Archaeoglobus fulgidus. Proc Natl Acad Sci USA 2002; 99:7536-41.
40. Omer AD, Lowe TM, Russell AG, Ebhardt H, Eddy SR, Dennis PP. Homologs of small
nucleolar RNAs in archaea. Science 2000; 288:517-22.
41. Veit K, Ehlers C, Ehrenreich A, Salmon K, Hovey R, Gunsalus RP, Deppenmeier U,
Schmitz RA. Global transcriptional analysis of Methanosarcina mazei strain Gö1 under
different nitrogen availabilities. Mol Genet Genomics 2006; 276:41-55.
42. Hüttenhofer A, Cavaille J, Bachellerie JP. Experimental RNomics: a global approach to
identifying small nuclear RNAs and their targets in different model organisms. Methods
Mol Biol 2004; 265:409-28.
43. Tjaden B. Prediction of small, noncoding RNAs in bacteria using heterogeneous data.
J Math Biol 2007; In press.
44. Urban JH, Papenfort K, Thomsen J, Schmitz RA, Vogel J. A conserved small RNA promotes discoordinate expression of the glmUS operon mRNA to activate GlmS synthesis.
J Mol Biol 2007; 373:521-8.
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RNA Biology
2007; Vol. 4 Issue 3