Hanah Margalit's research while affiliated with Hebrew University of Jerusalem and other places
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Publications (214)
Hypervirulent Klebsiella pneumoniae (hvKp) can infect healthy individuals, in contrast to classical strains that commonly cause nosocomial infections. The recent convergence of hypervirulence with carbapenem-resistance in K. pneumoniae can potentially create ‘superbugs’ that are challenging to treat. Understanding virulence regulation of hvKp is th...
In bacteria, determination of the 3’ termini of transcripts plays an essential role in regulation of gene expression, affecting the functionality and stability of the transcript. Several experimental approaches were developed to identify the 3’ termini of transcripts, however, these were applied only to a limited number of bacteria and growth condi...
Coinfection of HIV and multidrug-resistant tuberculosis (MDR-TB) presents significant challenges in terms of the treatment and prognosis of tuberculosis, leading to complexities in managing the disease and impacting the overall outcome for TB patients. This study presents a remarkable case of a patient with MDR-TB and HIV coinfection who survived f...
Coinfection of HIV and multidrug-resistant tuberculosis (MDR-TB) presents significant challenges in terms of the treatment and prognosis of tuberculosis, leading to complexities in managing the disease and impacting the overall outcome for TB patients. This study presents a remarkable case of a patient with MDR-TB and HIV coinfection who survived f...
Bacteria adapt to their host by mutating specific genes and by reprogramming their gene expression. Different strains of a bacterial species often mutate the same genes during infection, demonstrating convergent genetic adaptation. However, there is limited evidence for convergent adaptation at the transcriptional level. To this end, we utilize gen...
The envelope of Gram-negative bacteria is a vital barrier that must balance protection and nutrient uptake. Small RNAs are crucial regulators of the envelope composition and function. Here, using RIL-seq to capture the Hfq-mediated RNA-RNA interactome in Salmonella enterica, we discover envelope-related riboregulators, including OppX. We show that...
A main strategy of bacteria adapting to environmental changes is the remodeling of their transcriptome. Changes in the transcript levels of specific genes are due to combined effects of various regulators, including small RNAs (sRNAs). sRNAs are post-transcriptional regulators of gene expression that mainly control translation, but also directly an...
Small RNAs (sRNAs) exert their regulation posttranscriptionally by base pairing with their target mRNAs, often in association with the RNA chaperone protein Hfq. Here, integrating RNA-seq–based technologies and bioinformatics, we deciphered the Hfq-mediated sRNA-target interactome of enteropathogenic Escherichia coli (EPEC). The emerging network co...
The genomic revolution and subsequent advances in large-scale genomic and transcriptomic technologies highlighted hidden genomic treasures. Among them stand out non-coding small RNAs (sRNAs), shown to play important roles in post-transcriptional regulation of gene expression in both pro- and eukaryotes. Bacterial sRNA-encoding genes were initially...
Within-host adaptation is a hallmark of chronic bacterial infections, involving substantial genomic changes. Recent large-scale genomic data from prolonged infections allow the examination of adaptive strategies employed by different pathogens and open the door to investigate whether they converge towards similar strategies. Here, we compiled exten...
Bacterial small RNAs (sRNAs) are posttranscriptional regulators of gene expression that base pair with complementary sequences on target mRNAs, often in association with the chaperone Hfq. Here, using experimentally identified sRNA-target pairs, along with gene expression measurements, we assess basic principles of regulation by sRNAs. We show that...
Table S2. The Conservation of Proteins Comprising Different Flagella or Type III Secretion System Subunits in Different Bacterial Species, Related to Figure 4
Each row represents a single species from the STRING core genomes and each column represents one protein. The protein names are followed by the species of origin (Bacillus: B. subtilis prote...
We have previously described the existence of membranous nanotubes, bridging adjacent bacteria, facilitating intercellular trafficking of nutrients, cytoplasmic proteins, and even plasmids, yet components enabling their biogenesis remain elusive. Here we reveal the identity of a molecular apparatus providing a platform for nanotube biogenesis. Usin...
Bacterial RNase III plays important roles in the processing and degradation of RNA transcripts. A major goal is to identify the cleavage targets of this endoribonuclease at a transcriptome-wide scale and delineate its in vivo cleavage rules. Here we applied to Escherichia coli grown to either exponential or stationary phase a tailored RNA-seq-based...
In human, nearly half of the known microRNAs (miRNAs) are encoded within the introns of protein-coding genes. The embedment of these miRNA genes within the sequences of protein-coding genes alludes to a possible functional relationship between intronic miRNAs and their hosting genes. Several studies, using predicted targets, suggested that intronic...
The majority of mammalian genes contain one or more alternative polyadenylation sites. Choice of polyadenylation sites was suggested as one of the underlying mechanisms for generating longer/shorter transcript isoforms. Here, we demonstrate that mature mRNA transcripts can undergo additional cleavage and polyadenylation at a proximal internal site...
Small RNAs (sRNAs) are major post-transcriptional regulators of gene expression in bacteria. To enable transcriptome-wide mapping of bacterial sRNA–target pairs, we developed RIL-seq (RNA interaction by ligation and sequencing). RIL-seq is an experimental–computational methodology for capturing sRNA–target interactions in vivo that takes advantage...
Small RNAs (sRNAs) are central regulators of gene expression in bacteria, controlling target genes posttranscriptionally by base pairing with their mRNAs. sRNAs are involved in many cellular processes and have unique regulatory characteristics. In this review, we discuss the properties of regulation by sRNAs and how it differs from and combines wit...
Small RNAs (sRNAs) associated with the RNA chaperon protein Hfq are key posttranscriptional regulators of gene expression in bacteria. Deciphering the sRNA-target interactome is an essential step toward understanding the roles of sRNAs in the cellular networks. We developed a broadly applicable methodology termed RIL-seq (RNA interaction by ligatio...
Table S4. Common Motifs Identified in sRNA Target Sequence Sets, Related to Figures 4A–4D
Table S6. Summary of Genomic Elements Identified by RIL-Seq, Related to Figure 5A
Table S8. Strains, Deoxyribonucleotides, and Plasmids Used in This Study, Related to Experimental Procedures
Table S3. Previously Reported sRNA-Target Interactions Recovered by RIL-Seq, Related to Figure 3
Table S7. Predicted Base Pairing between sRNAs and Their Putative Targets, Related to Figure 6A
Mixed feedback loops combining transcriptional and post-transcriptional
regulations are common in cellular regulatory networks. They consist of two
genes, encoding a transcription factor and a small non-coding RNA (sRNA), which
mutually regulate each other's expression. We present a theoretical and
numerical study of coherent mixed feedback loops o...
Ndd1 activates the Mcm1-Fkh2 transcription factor to transcribe mitotic regulators. The anaphase-promoting complex/cyclosome activated by Cdh1 (APC/C(Cdh1)) mediates the degradation of proteins throughout G1. Here we show that the APC/C(Cdh1) ubiquitinates Ndd1 and mediates its degradation, and that APC/C(Cdh1) activity suppresses accumulation of N...
The human microbiome is dynamic and unique to each individual, and its role is being increasingly recognized in healthy physiology and in disease, including gastrointestinal and neuropsychiatric disorders. Therefore, characterizing the human microbiome and the factors that shape its bacterial population, how they are related to host-specific attrib...
Cells adapt to environmental changes by efficiently adjusting gene expression programs. Staphylococcus aureus, an opportunistic pathogenic bacterium, switches between defensive and offensive modes in response to quorum sensing signal. We identified and studied the structural characteristics and dynamic properties of the core regulatory circuit gove...
Most bacterial small RNAs (sRNAs) are post-transcriptional regulators of gene expression, exerting their regulatory function by base-pairing with their target mRNAs. While it has become evident that sRNAs play central regulatory roles in the cell, little is known about their evolution and the evolution of their regulatory interactions. Here we used...
Competing endogenous RNAs (ceRNAs) were recently introduced as RNA transcripts that affect each other’s expression level through competition for their microRNA (miRNA) coregulators. This stems from the bidirectional effects between miRNAs and their target RNAs, where a change in the expression level of one target affects the level of the miRNA regu...
Decoding of all codons can be achieved by a subset of tRNAs. In bacteria, certain tRNA species are mandatory, while others
are auxiliary and are variably used. It is currently unknown how this variability has evolved and whether it provides an adaptive
advantage. Here we shed light on the subset of auxiliary tRNAs, using genomic data from 319 bacte...
Small RNAs are integral regulators of bacterial gene expression, the majority of which act posttranscriptionally by basepairing with target mRNAs, altering translation or mRNA stability. 6S RNA, however, is a small RNA that is a transcriptional regulator, acting by binding directly to σ(70)-RNA polymerase (σ(70)-RNAP) and preventing its binding to...
DNA motifs and conservation patterns across species
Supplementary Figures S1–S15
DNA motifs' functional modules and genes in modules
Comparison of motif functional annotations to the literature
Evolutionary rewiring of regulatory networks is an important source of diversity among species. Previous evidence suggested substantial divergence of regulatory networks across species. However, systematically assessing the extent of this plasticity and its functional implications has been challenging due to limited experimental data and the noisy...
Functional modules constructed with different parameter sets
DNA Motif information: conservation, turnover and functions
Simulation test on the number of highly conserved genes
Functional modules for transcription factors, from experimental targets
Turnover of core target genes within functional modules
Comparing between functional modules with different parameters
Synonymous codons are unevenly distributed among genes, a phenomenon termed codon usage bias. Understanding the patterns of
codon bias and the forces shaping them is a major step towards elucidating the adaptive advantage codon choice can confer
at the level of individual genes and organisms. Here, we perform a large-scale analysis to assess codon...
Two major classes of small regulatory RNAs--small interfering RNAs (siRNAs) and microRNA (miRNAs)--are involved in a common RNA interference processing pathway. Small RNAs within each of these families were found to compete for limiting amounts of shared components, required for their biogenesis and processing. Association with Argonaute (Ago), the...
Genome sequencing of various individuals or isolates of the same species allows studying the polymorphism level of specific proteins and protein domains. Here we ask whether domains that are known to be involved in mediating protein-protein interactions show lower polymorphism than other domains. To this end we take advantage of a recent genome seq...
Heat map of the p-values of Kolmogorov-smirnov tests comparing pN/pS between a set of residues defined by a resolution level and a complementary set, when mutations are determined by different thresholds, as in Figure S1.
(DOCX)
The CRISPR-Cas system represents an RNA-based adaptive immune response system in prokaryotes and archaea. CRISPRs (clustered regularly interspaced short palindromic repeats) consist of arrays of short repeat-sequences interspaced by nonrepetitive short spacers, some of which show sequence similarity to foreign phage genetic elements. Their cistroni...
Many protein-protein interactions are mediated by domain-motif interaction, where a domain in one protein binds a short linear motif in its interacting partner. Such interactions are often involved in key cellular processes, necessitating their tight regulation. A common strategy of the cell to control protein function and interaction is by post-tr...
Counts and statistical significance of the coupling between domain-motif interactions and phosphorylations.
(PDF)
Statistical significance for the PDZ double-switch analysis.
(PDF)
Proteins that are predicted to be involved in ‘double switches’ based on experimental protein-protein interaction data.
(PDF)
Database of interaction-regulation units for
Homo sapiens
.
(XLS)
Disorder levels of the various motifs.
(PDF)
Database of interaction-regulation units for Saccharomyces cerevisiae.
(XLS)
The disordered contexts of the motifs.
(PDF)
Statistical significance for the evolutionary path analysis.
(PDF)
Phylogenetic traces of interaction-regulation unit evolution.
(PDF)
Identification of human protein segments that display a dual motif that can act as a phosphorylation double switch for SH3 and SH2 domains or for SH2 and WW domains.
(PDF)
Phosphorylation specificity switch for proteins containing domains of the PDZ family.
(PDF)
![Figure S3. No correlation between Average Nc and CAI ave values. [A]...](publication/293984542/figure/fig2/AS:669383282139160@1536604819900/Figure-S3-No-correlation-between-Average-Nc-and-CAI-ave-values-A-The-average-Nc-value_Q320.jpg)
It is widely acknowledged that synonymous codons are used unevenly among genes in a genome. In organisms under translational selection, genes encoding highly expressed proteins are enriched with specific codons. This phenomenon, termed codon usage bias, is common to many organisms and has been recognized as influencing cellular fitness. This sugges...
Table S1 - features and characteristics of the prokaryotes included in this study. This file contains data and annotations of the organisms included in the analysis (nam, tax ID, CAIave, median CAI, coefficient of variation (of CAI), Ncdiff, average Nc, environmental properties, if it is the representative subspecies of the species, super kingdom,...
Motivation:
Over the past decade, deciphering the roles of microRNAs (miRNAs) has relied heavily upon the identification of their targets. Most of the targets that were computationally and experimentally characterized were evolutionarily conserved 'seed' targets, containing a perfect 6-8 nt match between the miRNA 5(')-region and the messenger RNA...
The fission yeast clade—comprising Schizosaccharomyces pombe, S. octosporus, S. cryophilus, and S. japonicus—occupies the basal branch of Ascomycete fungi and is an important model of eukaryote biology. A comparative annotation of
these genomes identified a near extinction of transposons and the associated innovation of transposon-free centromeres....
[This corrects the article on p. e1000010 in vol. 4.].
Bacterial small noncoding RNAs have attracted much interest in recent years as posttranscriptional regulators of genes involved
in diverse pathways. Small RNAs (sRNAs) are 50 to 400 nucleotides long and exert their regulatory function by directly base
pairing with mRNA targets to alter their stability and/or affect their translation. This base pair...
Computational identification of putative microRNA (miRNA) targets is an important step towards elucidating miRNA functions. Several miRNA target-prediction algorithms have been developed followed by publicly available databases of these predictions. Here we present a new database offering miRNA target predictions of several binding types, identifie...
Many protein-protein interactions (PPIs) are mediated by protein domains. The structural data of multi-domain PPIs reveal the domain pair (or pairs) that mediate a PPI, and implicitly also the domain pairs that are not involved in the interaction. By analyzing such data, preference relations between domain pairs as interaction mediators may be reve...
Schematic representation of miR-M23-2 and miR-m21-1 binding sites within the CXCL16 3′UTR. Shown are the sites predicted by RepTar version 1.1, based on the statistical profiles of repeating elements in the 3′UTR. The miRNA is indicated in red on top of the alignment. For miR-M23-2 there is an additional full seed match at position 221, which was n...
Micro (mi)RNAs are small non-coding RNAs that regulate the expression of their targets' messenger RNAs through both translational inhibition and regulation of target RNA stability. Recently, a number of viruses, particularly of the herpesvirus family, have been shown to express their own miRNAs to control both viral and cellular transcripts. Althou...
Identification of a putative cellular target of miR-M23-2. A. CXCL16 is regulated by miR-M23-2, but not by miR-m21-1. NIH-3T3 fibroblasts were co-transfected with a bulged luciferase sensor for miR-M23-2 or a luciferase reporter construct containing the entire CXCL16 3′UTR, and with the indicated miRNA oligonucleotides mimics or negative control si...
Genetic interactions between genes reflect functional relationships caused by a wide range of molecular mechanisms. Large-scale genetic interaction assays lead to a wealth of information about the functional relations between genes. However, the vast number of observed interactions, along with experimental noise, makes the interpretation of such as...
Legionella pneumophila is a Gram-negative opportunistic human pathogen that infects and multiplies in a broad range of phagocytic protozoan and mammalian phagocytes. Based on the observation that small regulatory RNAs (sRNAs) play an important role in controlling virulence-related genes in several pathogenic bacteria, we attempted to identify sRNAs...
The detailed rate equations for the model, describing the part of the SOS system that was used in the analysis.
(0.03 MB PDF)
Background:
DNA damage in Escherichia coli evokes a response mechanism called the SOS response. The genetic circuit of this mechanism includes the genes recA and lexA, which regulate each other via a mixed feedback loop involving transcriptional regulation and protein-protein interaction. Under normal conditions, recA is transcriptionally represse...
Citations
... The potentially weakened immune system of people living with HIV (PLHIV) being infected with MDR-TB, the possibility of drug-drug interactions, and the magnified side effects of both treatments pose significant health challenges. It not only amplifies the clinical complexities in managing each condition individually but also introduces unique and compounded challenges at the intersection of MDR-TB and HIV/AIDS [67]. A recent study in South Africa showed that patients being treated for both HIV and MDR-TB had an 8% treatment completion proportion (11/137) ...
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... Agnodice constitutes the first comprehensive database of experimentally supported bacterial sRNA-RNA interactions, currently hosting the largest number of interactions (39,600), as evidenced by a wide assortment of methodologies. Today, a plethora of research projects and laboratories are pushing the envelope of bacterial small RNA research by actively pursuing and realizing novel experimental and computational techniques (33,(37)(38)(39)(40)(41)(42)(43)(44). Breakthrough works from the last few years demonstrate not only the importance of bacterial sRNAs but also their beauty and complexity. ...
... To benchmark our approach, we applied ChimericFragments to seven published datasets, involving six different organisms and three different experimental pipelines, i.e. V. cholerae (RIL-seq, ( 27 )), Escherichia coli ( E. coli , RIL-seq and CLASH, ( 13 ,49 )), enteropathogenic E. coli (RIL-seq, ( 50 )), Pseudomonas aeruginosa (RIL-seq, ( 51 )), Salmonella enterica (RIL-seq, ( 52 )) and Bacillus subtilis (LIGR-seq, ( 53 )). In all cases, ChimericFragments recovered significantly more interactions than initially reported in the respective studies ( Supplementary Figure S7 c-i). ...
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... Hfq-mediated sRNA-mRNA base-pairing can activate the RNA targets [6] or induce their degradation [7]. Blueprints of many Hfq-dependent sRNA regulatory networks can be established beyond the known targetomes using genome-wide approaches, such as RNA interaction by ligation and sequencing (RIL-seq), global sRNA target identification by ligation and sequencing (GRIL-Seq), and UV crosslinking, ligation, and sequencing of hybrids (CLASH) [8][9][10][11]. ...
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... Agnodice constitutes the first comprehensive database of experimentally supported bacterial sRNA-RNA interactions, currently hosting the largest number of interactions (39,600), as evidenced by a wide assortment of methodologies. Today, a plethora of research projects and laboratories are pushing the envelope of bacterial small RNA research by actively pursuing and realizing novel experimental and computational techniques (33,(37)(38)(39)(40)(41)(42)(43)(44). Breakthrough works from the last few years demonstrate not only the importance of bacterial sRNAs but also their beauty and complexity. ...
... These abilities allow bacteria to transition between a harmless commensal state and a potentially harmful pathogenic state, affecting the host's immune responses and the outcome of diseases [47]. By examining and analyzing various aspects of the infection process in experimental settings that closely resemble nearephysiological interactions, such as pathogen invasion, colonization, and the host's immune response, we can gain a solid knowledge foundation for the development of innovative strategies for manipulating the microbiome to restore microbial balance, enhance immune function, and mitigate the progression of diseases. ...
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... (5) hfq-is downregulated by CRP (Fig 5, Edge 6) [45] and encodes a key chaperone of RNA folding that is involved in the regulation of interactions between small non-coding RNAs and their targets. As an important chaperone, hfq is involved in response to a large variety of conditions and stresses [46,47]; (6) cycA-encodes a D-serine/ D-alanine/glycine transporter that is upregulated by CRP (Fig 5, Edge 7). (7) glcC-encodes a TF and is upregulated by CRP (Fig 5, Edge 8) [48]. ...
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... Furthermore, it was found that in BNTs is present a conserved calcineurin-like phosphodiesterase protein, namely YmdB, retained essential for both nanotube production and intercellular molecular trade [54]. More recently, other components enabling the biogenesis of BNTs, have been identified in a molecular apparatus (the flagellar body proteins) which provides a platform for nanotube biogenesis [59]. Moreover, although several genes involved in the BNTs formation had been reported, the pivotal role of a specific sigma factor and of some autolysins in BNTs formation was very recently investigated and elucidated in B. subtilis [60]. ...
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... As RNase III has a role in the stabilization of sodA mRNA in the absence of stress, we investigated whether this effect could be due to an RNase III processing event that may stabilize the sodA mRNA. An in vitro RNase III cleavage assay showed that the full-length sodA mRNA is cleaved by RNase III at multiple positions, including one minor cleavage within the 5 -UTR (nts +28 relative to the transcription start site, Figure S8), which is similar to the unique in vivo cleavage site in the sodA mRNA previously identified [33]. In summary, RNase III is required for sodA mRNA stabilization and can cleave the sodA mRNA 5 -UTR in vitro, supporting previous in vivo observations. ...
... Unlike other Gram-negative bacteria, C. jejuni does not encode RNase E, responsible for processing many 3' untranslated region (UTR)-derived sRNAs in Gammaproteobacteria 40,41 , and instead encodes RNase Y 8 . Double-strand-specific RNase III is also emerging as an important player in sRNA processing and regulation [42][43][44][45] , and is required for ribosomal and CRISPR RNA biogenesis in C. jejuni 28,46,47 . We measured CJnc230 expression in total RNA from a panel of RNase-deficient C. jejuni deletion mutant strains by northern blot (Supplementary Fig. 1b), which revealed that RNase III (rnc, Cj1635c), RNase Y (rny, Cj1209), and the 3'-5' exoribonuclease polynucleotide phosphorylase (PNPase, pnp, Cj1253) affect its expression ( Fig. 2a and Supplementary Fig. 1b). ...
