Global analysis of transcriptional regulators in Staphylococcus aureus
© Ibarra et al; licensee BioMed Central Ltd. 2013
Received: 21 October 2012
Accepted: 12 February 2013
Published: 26 February 2013
Staphylococcus aureus is a widely distributed human pathogen capable of infecting almost every ecological niche of the host. As a result, it is responsible for causing many different diseases. S. aureus has a vast array of virulence determinants whose expression is modulated by an intricate regulatory network, where transcriptional factors (TFs) are the primary elements. In this work, using diverse sequence analysis, we evaluated the repertoire of TFs and sigma factors in the community-associated methicillin resistant S. aureus (CA-MRSA) strain USA300-FPR3757.
A total of 135 TFs and sigma factors were identified and classified into 36 regulatory families. From these around 43% have been experimentally characterized to date, which demonstrates the significant work still at hand to unravel the regulatory network in place for this important pathogen. A comparison of the TF repertoire of S. aureus against 1209 sequenced bacterial genomes was carried out allowing us to identify a core set of orthologous TFs for the Staphylococacceae, and also allowing us to assign potential functions to previously uncharacterized TFs. Finally, the USA300 TFs were compared to those in eleven other S. aureus strains including: Newman, COL, JH1, JH9, MW2, Mu3, Mu50, N315, RF122, MRSA252 and MSSA476. We identify conserved TFs among these strains and suggest possible regulatory interactions.
The analysis presented herein highlights the complexity of regulatory networks in S. aureus strains, identifies key conserved TFs among the Staphylococacceae, and offers unique insights into several as yet uncharacterized TFs.
Staphylococcus aureus is a facultative human pathogen and the casual agent of a diverse array of diseases, including superficial skin and wound-related tissue infections, food poisoning, bacteremia, endocarditis and pneumonia. This organism produces a diverse array of virulence factors, including toxins, adhesins, colonization and biofilm factors. S. aureus has obtained notoriety in recent years due to the appearance and worldwide spread of antibiotic resistant strains. Hospital associated (HA) and community associated (CA) infections caused by methicillin-resistant S. aureus (MRSA) have become a major public health concern, particularly for CA-MRSA infections as they cause life threatening disease in otherwise healthy individuals with no pre-existing risk factors . Furthermore, CA-MRSA strains are replacing HA-MRSA strains in clinical settings, increasing the risk of transmission not only to patients but also into healthy individuals in the community (reviewed in ). As virulence determinant production is very tightly regulated in S. aureus, a thorough understanding of its regulatory network is necessary to fully comprehend the pathogenic processes of this bacterium. Additionally, exploring the regulatory differences between CA-MRSA and other MRSA strains may aid our understanding of the increase in virulence observed amongst community-associated isolates.
The relatively small size of Staphylococcal genomes, and their adaptability, suggests that these bacteria have a high degree of genome plasticity, depending on their environment [3, 4]. Given the high number of virulence factors present in these bacteria, and the niche-specific role many of them play during different stages of the infectious process, gene expression must be finely tuned in order to efficiently coordinate their expression, and also continue to preserve energy pools. In this context, DNA-binding transcription factors (TFs) play an important regulatory role by either repressing or activating genes in response to environmental and physiological conditions.
Even though diverse strains of S. aureus have been extensively studied, and subjected to genome sequencing, the function of a large proportion of their genes remains unidentified. In this work, we define the TF repertoire for the CA-MRSA strain USA300-FPR3757 and classify it into regulatory families. We have evaluated the orthologous distribution of these elements in other sequenced bacterial genomes using the repertoire of TFs identified in USA300, and identified a core set of regulators for both the Firmicutes phylum, and the Staphylococacceae group. Finally, we examine the conservation of 135 USA300 TFs amongst 11 other S. aureus strains, identifying a key group of regulators that display a high degree of conservation, including many that have previously been demonstrated to play a role in virulence gene regulation. We also highlight cases whereby TFs are absent, or altered within strains, suggesting changes in the wiring of regulatory networks in individual isolates.
Identification of TFs and σ factors in S. aureusUSA300
Possible role for uncharacterized TFs in S. aureus USA300
Identities and comments
Present in the ACME element
YwqM (30.2%) and GltR (27.9%), in B. subtilis. The latter appears to be involved in glutamate synthase expression.
PtxR of Pseudomonas aeruginosa PAO1 (41.5%) and Yersinia pestis (38.7%). Activates the expression of exotoxins and represses the expression of quorum sensing related genes.
Btr (24.5%) from B. subtilis. One-component regulator that controls siderophore transport
TreR (37%), involved in the regulation of trehalose related genes in B. subtilis. It is encoded divergent to purine synthesis genes.
YesN (38.4%) and DegU (35.8%) from B. subtilis. The latter is involved in the expression of proteases and biofilm.
MnaR (25%) from B. subtilis
LutR (44.4%), involved in regulation of lactate and biofilm in B. subtilis. It has a UbiC transcription regulator-associated (UTRA) domain.
LicR (28.5%) from B. subtilis. Regulates the transport and degradation of oligomeric beta-glucosides
YgzD (46%) B. subtilis
No identity to characterized proteins
YdeL (36%) and GabR (32.3%) both from B. subtilis. GabR regulates the expression of GABA synthesis genes. It also has some identity to S. aureus NorG (23%). It has a pyridoxal phosphate (PLP)-dependent aspartate aminotransferase domain.
This is the first gene in a putative operon with a pyridine nucleotide-disulphide oxidoreductase.
E. coli OxyR (29.4%), positive regulator for a hydrogen peroxide-inducible regulon. Possible CcpC homolog, involved in regulation of TCA.
IolR (30.9%), repressor or the myo-inositol operon in B. subtilis. Its genomic context shows that it may regulate genes involved in fructose metabolism.
Toxin-antitoxin systems. These systems may contribute to the preservation of plasmids and genetic islands, however the role of many of them is still unknown
CytR (25%), regulator of the citrate synthase genes in B. subtilis. In S. aureus it is divergent to isopropylmalate synthase involved in Leu and pyruvate metabolism.
B. subtilis YabR (42%), putative polyribonucleotide nucleotidyl transferase
B. subtilis ComK (33.9%), required for genetic competence
YdgJ (35.4%), B. subtilis
Rpc (33.7%) from B. subtilis bacteriophage phi 105. Involved in the regulation of lysogeny.
YmfC (34.3%), B. subtilis. It has a UbiC transcription regulator-associated (UTRA) domain.
YmfK (65%), B. subtilis
YmfM (31.25%) B. subtilis
No identity to characterized proteins
LuxR-like protein with identity to DesR (43.2%), responsible for thermosensing and signal transduction at low temperatures in B. subtilis. Also has identity to YvfU (45%) from B. subtilis
No identity to characterized proteins
No identity to characterized proteins
AarP (30.8%), involved in regulation of 2'-N-acetyltransferase in Providencia stuartii.
28% identity with S.aureus ArgR. In operon with a DNA repair protein
B. subtilis YtrA (39.45%), possible repressor of an operon for a putative ATP-binding cassette transport system involved in acetoin utilization. YtrA is an additional regulator of cell envelope stress responses in B. subtilis.
RinB (76%) from phage 11. Activates int gene expression
No identity to characterized proteins
LexA (28%), SOS regulator in E. coli
B. subtilis YodB (38.46%), regulation of yocJ (azoR1) after exposure to thiol-reactive compounds. A similar gene in B. subtilis regulates formaldehyde detoxification via hxlAB. In S. aureus it is not close to these genes, even though they are present in the genome.
ManR_(23.6%), mannose utilization in B. subtilis
AdhR (38%) B. subtilis. Transcriptional regulator involved in the response to aldehyde stress.
YwoH (31.6%) from B. subtilis
E. coli YijO (28.6%), might be involved in the regulation of genes encoding enzymes related to PTS systems
No identity to characterized proteins
No identity to characterized proteins. Divergent to 2 multidrug transport proteins (emrAB homologs)
Bears a LytTR domain, which is an only recently characterized family.
B. subtilis YxbF (42.4%). In S. aureus it is in an operon with a CorA Mg transporter
CueR (42.8%), involved in copper induction in B. subtilis.
36% identical to BltR, B. subtilis, and MerR (31%), S. aureus. The former is involved in response to structurally dissimilar drugs, while the latter is on a plasmid specifying resistance for mercurial compounds.
B. subtilis YuaC (55.4%)
Similar to B. subtilis YvnA (35.8%), (29%) and AdcR from Streptococcus pneumoniae. AdcR is able to sense metals for the regulation of zinc uptake proteins related genes encoding cell-surface zinc-binding pneumococcal histidine triad proteins and AdcAII (laminin binding). Also has a 33% identity to SarZ
MhqR (41.5%) regulates multiple dioxygenases/glyoxalases and an azoreductase that confer resistance to 2-methylhydroquinone and catechol in B. subtilis
No identities to characterized proteins. Divergent to operon encoding mmpL (transporter) and Feo iron dependent transporters
B. subtilis YxbF (31.6%).
SlmA (26.2%) in Vibrio parahaemolyticus. SlmA proteins are involved in nucleoid occlusion systems in E. coli. In S. aureus it is in an operon with genes encoding an oxidoreductase, an amidohyrolase and a hydrolase.
No identity to characterized proteins.
PetP, (33.06%), necessary for photosynthetic and respiratory growth in Rhodobacter capsulatus
No identity to characterized proteins.
ImmR (46% identity), involved in mobilization of the genetic element ICEB1 in B. subtilis
PadR (37.5%), repressor of phenolic acid response genes in B. subtilis
Distribution of USA300 TF homologs in eubacterial species
Many bacterial TFs involved in key cellular processes are essential to the cell and are highly conserved. We hypothesized that a subset of the 135 TFs identified in USA300 would be conserved across eubacterial organisms. To test this hypothesis we set out to identify which TFs shared an orthologous protein in other bacterial phyla. A total of 1209 bacterial genomes were studied, comprising strains from the following phyla: Acidobacteria, Actinobacteria, Aquificae, Bacteroidetes, Chlamydiae, Chlorobi, Chloroflexi, Chrysiogenetes, Cyanobacteria, Deferribacteres, Deinococcus-Thermus, Dictyoglomi, division WWE1, Elusimicrobia, Fibrobacteres, Firmicutes, Fusobacteria, Gammatimonadetes, Nitrospirae, Planctomycetes, Proteobacteria, Spirochaetes, Synergistetes, Tenericutes, Thermobaculum, Thermatogae and Verrucomicrobia.
As such, by using the TFs found in S. aureus USA300 as a scaffold to interrogate other sequenced bacterial genomes, we were able to identify: (i) TFs that are conserved in all the bacterial phyla, suggesting an ancient origin and critical cellular function, (ii) those regulators found mainly in the Firmicutes, and (iii) regulators found exclusively in the Staphylococacceae.
Comparison of TFs between S. aureusstrains
A total of 112 TFs were identified as being present in all S. aureus strains, including regulators of genes involved in metabolic (ArcR, Fur, HutR, GntR, GlnR, CcpA, ArgR, ArcR, FeoA, Fur, PerR, FemC, TreR, GapR, LacR, FapR, CcpA, PurR, HisR, and multiple TCS) and virulence processes (AgrA, SarA, SarR, SarS, SarV, SarX, SarY, SarZ, Rot and MgrA). The high degree of conservation of these TFs probably emphasizes the need for specific and precise regulation of genes involved in these key physiological processes. In addition, we found TFs in this group that are associated with genome homeostasis such as LexA and HU that respond to DNA damage and structure, respectively. Unsurprisingly, given their role in transcription processes, all the σ factors (σA, σB, σH and σS) were conserved across all strains.
Conversely, a number of TFs were found in most strains, but were absent in one or two. The absence of these TFs suggests that their loss leads to a difference in the strain specific regulation of important pathways. Amongst this group are the TCS-RRs. Fourteen of the sixteen S. aureus TCS are conserved in all strains analyzed, however ArlR, for example, is present, yet truncated, in strain N315. Similarly, the uncharacterized SAUSA300_1220 is truncated in strain MRSA252; and both SAUSA300_1220 and SrrA are absent from the bovine pathogen RF122 (Figure 2). Interestingly, for these latter two regulators, the sensor histidine kinase is also missing. Additionally, a rare event occurs where the TCS KdpDE is duplicated on SCCmec II; thus strains N315, Mu50, JH1, JH9, Mu3 and MRSA252 are unique in carrying two copies of this regulatory system. The occurrence of this duplication has previously been observed , however its biological significance is not yet clear.
In the context of non-TCS-RR, other TFs are also variable across S. aureus strains, including SAUSA300_0063, which is only found in USA300. This TF is a likely duplication of the ArgR arginine repressor, and is encoded on the arginine catabolic mobile element (ACME), which is present only in USA300 strains and is linked to SCCmec IV . By far, the most variability within a family of TFs was observed for the Xre-like elements. This family includes regulators in Eukaryotes, Archaea and Bacteria, and is evolutionarily related to the bacteriophage regulators Cro and cI . Our analysis showed that S. aureus USA300-FPR3757 has 13 putative members of this family. To our knowledge XdrA, which is present in all strains analyzed and serves as an activator of the virulence factor protein A , is the only member of this family that has been characterized. In contrast to some of the Xre-like proteins found herein, XrdA is not encoded on or near a phage-related element. Other Xre regulators also exist that are similarly unassociated with lysogenic bacteriophages, including SAUSA300_0804, SAUSA300_2640 and SAUSA300_0998. In total, five Xre-like TFs were found in all S. aureus strains, and appear to be unassociated with phage-like elements. It is tempting to suggest that the presence or absence of these Xre elements could be considered a genetic fingerprint for each of the strains, and may influence regulatory network in subtle yet wide-reaching ways.
The overall aim of this study was to gain insight into the composition and conservation of TFs in the Staphylococacceae, specifically in the major human pathogen, S. aureus. First we detected TFs in the USA300-FPR3757 strain, identifying 135 elements belonging to 36 different regulatory families. Of note, almost half of these (58 out of 135, or 42.9%) have yet to be characterized. Herein we were able to propose possible roles for most of them, leaving only 9 without ascribed or predicted functions.
The most abundant TFs in this strain belonged to the MarR family, which includes the Sar-like subfamily . One such TF (SAUSA300_2452) was of particular interest as it showed 33% identity with SarZ over 64% of the length of the protein, as determined using BLASTP, suggesting that it might be a new member of this family. In order to corroborate whether this protein is related to the Sar family we generated a phylogenetic tree with all known Sar and MarR proteins found in the USA300 strain and compared them with the crystal structure of MgrA. As seen in Additional file 2: Figure S1, MarR-like TFs were grouped in three clades: one including SarX, TcaR and four non-characterized MarR proteins; a second included SarA, SarY, SarR, SarS, SarU, SarV and Rot; and the third included MgrA, SarZ and SAUSA300_2452. From this analysis it seems that SAUSA300_2452 is phylogenetically related to SarZ and MgrA, suggesting it may belong to this subfamily.
Given the adaptability of S. aureus to multiple environments it is perhaps no surprise to find that TCS-RR family was one of the most abundant families, with 16 members. Despite the fact that this group of proteins has been widely studied, two members remain uncharacterized, SAUSA300_1220 and SAUSA300_0217. SAUSA300_1220 shares homology with B. subtilis DesR (43% identity over 99% of the protein, as determined using BLASTP), which is involved in sensing changes in temperature and regulating the expression of genes that respond to this environmental cue . Of note, in gamma-proteobacteria this role is accomplished by the histone-like protein H-NS and other related factors, which are seemingly absent in the firmicutes . Indeed, in S. aureus there is only one protein related to the histone-like family, suggesting that regulation of the thermal response is achieved by other TFs, which may include SAUSA300_1220. SAUSA300_0217 has some identity to DegU (35.8% identity over 42% of the protein, as determined using BLASTP) from B. subtilis, which is involved in the modulation of protease expression and biofilm formation. Importantly, there is some suggestion that this system, or rather its counterpart in strain COL, is expressed during anaerobiosis .
We also used the USA300 TFs as a scaffold to define how conserved these regulators are within eubacterial species. This analysis showed that nine TFs have orthologues in almost all of the 1209 genomes analyzed. This suggests that these proteins have an important role in cell fitness, and have a common ancestral origin. Included in this group are: SAUSA300_1521, the primary sigma factor σ70 (σA) that drives house-keeping gene expression; and the histone-like protein HU (SAUSA300_1362), which is important in controlling DNA structure . Also included in this group is SAUSA300_1347 (BirA), which is involved in regulation and biotinylation of the essential metabolic factor CoA . CidR (SAUSA300_2480) regulates the expression of holin/anti-holin complexes involved in peptidoglycan synthesis, and is therefore important for bacterial survival, at least in S. aureus strains . SAUSA300_1632 is a NrdR orthologue that regulates the expression of ribonucleotide reductases, necessary for DNA and RNA synthesis . HrcA (SAUSA300_1542) is an important regulator of proteins involved in the heat-shock response in Bacillus subtilis. Though less conserved than the other TFs in group 1, ArlR (SAUSA300_1308) is still preserved in many bacterial phyla. ArlR is a two-component response regulator that controls the expression of 114 genes in S. aureus, including those involved in cell division and growth .
We also identified a group of regulatory proteins whose orthologues are conserved within most Firmicutes, and are involved in processes such as metabolism (GapR, TreR, GlnR, HutR, Hex, RpiRC, ScrR), stress response (NsaR, GraR, MepR) and virulence (AgrA, SarZ, SaeR, IcaR, Rsp). The prevalence of TFs related to metabolism and stress in so many Firmicutes would be expected as this suggests a common origin. It is interesting to note that while highly conserved regulators are involved in key cellular processes, TFs that are phylum specific are involved in more specialized functions i.e. stress response and virulence. For example, it is possible that in non-pathogenic organisms, those TFs known to regulate virulence genes in other species serve to control genes for niche adaptation or symbiosis.
At the most specific level, we defined those TFs that were conserved uniquely in the Staphylococacceae. Most of the TFs in this group are related to virulence and environment adaptation, including the Sar family of proteins, the alternative sigma factor SigS, and some elements involved in metabolism. Collectively, and to our knowledge, this is the first global study that circumscribes the TFs for the Firmicutes, and more specifically, the Staphylococacceae.
Another of our objectives was to define how conserved TFs are across multiple, well-characterized S. aureus strains. We first identified the TFs for eleven additional strains (Figure 4, and data not shown) and then compared them with those in USA300. The majority of the TFs were conserved across all strains (83%), which is largely comprised of those that are part of the core Staphylococcal TF suite. The absence of the other 17% of regulatory proteins indicates that these are not central for survival or pathogenesis, and may be responsible for subtle, strain specific, fine-tuning of gene expression patterns. For instance, SAUSA300_0063 is a Crp-like TF encoded in the ACME region. ACME has been found only in USA300 strains, and is thought to play a role in virulence [46, 57]. All known USA300 strains have this genetic element, supporting its role in virulence processes and/or transmission. In contrast, Rbf, an AraC-like protein that positively regulates biofilm formation  is present in all strains except MRSA252. This exemplifies our contention that differences in regulatory networks adapt to strain specific process. For example, MRSA252 is a robust biofilm forming isolate, yet is still capable of undergoing this process in the absence of Rbf. This suggests that this process is multifactorial, involving many different regulators, and is adaptable within strains to individual growth or pathogenic environments.
The biggest difference in TFs amongst Staphylococcal strains was observed in phage related regulators. These demonstrated the most variability, which is unsurprising, as each strain has acquired variable phage content over time. Despite the fact that they are located on phage elements, some have developed a key role in the regulation of virulence genes in the core chromosome. Such is the case of XdrA, which regulates the expression of protein A, an important immune evasion virulence factor. Moreover, some TFs are located in the vicinity of putative toxin-antitoxin systems, e.g. SAUSA300_2640; such systems have been suggested to contribute to the preservation of plasmids and genetic islands . Additionally, one of these TFs (SAUSA300_0998) is located close to a putative putrescine secretion system, possibly forming an operon, suggesting it might be involved in its regulation.
TFs specific to USA300 and RF122
TFs present only in RF122
USA300 TFs absent in RF122
In summary, the analysis presented herein demonstrates the incredible complexity of regulatory networks and gene regulation in S. aureus, and offers unique insights into many as yet uncharacterized TFs in this important human pathogen. A comparison of S. aureus TFs with those of other bacterial phyla reveals two main types of TF in Staphylococci. The first group represents a core of regulators, present in common ancestors of diverse bacteria that participates in the regulation of key cellular processes. The second group represents TFs whose function seems to be genus/species specific (e.g. virulence gene regulators and those for specific metabolic requirements). Therefore we propose that TFs in group 4 forms the core set of TFs in the Staphylococcaceae. Included in this group are most the Sar regulators, which are part of the MarR family, and other, as yet uncharacterized proteins. Additionally, we focused on the differences amongst well-characterized S. aureus strains and found absence of TFs that might dictate changes in regulatory networks for each isolate. Finally, the similarities and differences in TF content between the human pathogen USA300 and the bovine pathogen RF122 were determined. Previous reports have shown that the expression of virulence factors amongst bovine and human isolates is different, and here we observed differences in the TFs content for these two strains. It is possible that some of these elements are involved in differentially regulating virulence factors, perhaps through modulation of known elements such as AgrA and SarA.
Identification of DNA-binding transcription factors
The complete genomes of twelve S. aureus strains were obtained from ftp://ftp.ncbi.nlm.nih.gov/genomes/Bacteria. Open reading frames that encode predicted protein sequences, i.e. the proteome in all bacteria, were considered as annotated genes. In order to identify the repertoire of TFs in S. aureus strains, domain assignations associated to DNA-binding regions in the Superfamily database (25-Apr-2010 version), and others identified and annotated in PFAM  were used. Additionally, family-specific Hidden Markov Models (HMM) constructed from three bacterial models: Escherichia coli K-12, Bacillus subtilis, and Corynebacterium glutamicum were used to search S. aureus genomes. Briefly, 90 family-specific HMMs previously reported for E. coli K-12  and 57 family-specific HMMs from B. subtilis were used to scan complete genome sequences (E-value threshold of 10-3), with the “hmmsearch” module from the HMMer suite of programs (http://hmmer.janelia.org/). These HMMs were constructed using the previously identified TF families in E. coli K-12 and B. subtilis as seeds, considering the DNA-binding domain (DBD) sequence (around 60 amino acids) of every protein from multiple families. S. aureus USA300 proteome sequences were scanned with these HMMs, and proteins with less than 60% coverage in the DNA-binding region against their corresponding HMM were excluded. Finally, regulators deposited in the DBD database  were also considered as potential DNA-binding TFs.
In order to evaluate the distribution of TFs and their corresponding orthologues across all bacterial genomes, a hierarchical average linkage-clustering algorithm was applied with a Manhattan correlation distance as a similarity measure. Analyses were performed using the program Mev4 (multi-experiment viewer; PMID:12613259). In order to determine the relative abundance of TFs and their orthologues, we calculated the fraction of genomes in the group that had at least one member versus the number of representative organisms. Thus, the following formula was considered: relative abundance by phylum (total number of orthologues identified)/(total number of organisms by phylum). Thus, a value of 1 corresponds to presence and 0 represents absence. Because our aim was to evaluate the taxonomical distribution of orthologues proteins, 27 taxonomical phyla corresponding to eubacteria were considered.
In order to achieve comparative analysis strain USA300-FPR3757 was used for the classification of TFs into evolutionary families. This was based on PFAM annotations, and corroborated using BLAST searches (using default conditions) against well-annotated protein families.
Comparison of ORFomes from different S. aureusstrains
Based on the USA300-FPR3757 ORFome, we searched for the presence and absence of TFs in eleven different strains, including: Newman, COL, JH1, JH9, MW2, Mu50, Mu3, N315, RF122, MRSA252 and MSSA476. This comparison was achieved by sequence analysis using the Comprehensive Microbial Resources (CRM) database from JCVI (http://cmr.jcvi.org/tigr-scripts/CMR/CmrHomePage.cgi), and confirmed by BLAST searches.
Additionally, in order to evaluate the phylogenetic distribution, the S. aureus TF repertoire was used to identify orthologous proteins in 1209 sequenced eubacterial strains. Orthologous relationships were identified based on BLASTP reciprocal best hits, with an E-value cut-off of ≤ 1e-6, as described elsewhere . Finally, the phylogenetic distribution of each TF was evaluated based on a hierarchical cluster analysis.
This work was supported by grants IN-209511 (EP-R) from DGAPA-UNAM, 155116 (EP-R) from the National Council for Science and Technology (CONACYT) and AI080626 (LNS) from the National Institute of Allergies and Infectious Disease.
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