Genome-wide Mapping of Transcriptional Start Sites Defines an Extensive Leaderless Transcriptome in Mycobacterium tuberculosis

Cortes, Teresa; Schubert, Olga T.; Rose, Graham; Arnvig, Kristine B.; Comas, Iñaki; Aebersold, Ruedi; Young, Douglas B.

doi:10.1016/j.celrep.2013.10.031

Cited by 290 publications

(437 citation statements)

References 64 publications

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“…(17). The sequences corresponding to −45 bp upstream and +5 bp downstream from the TSS were extracted from reference H37Rv sequence.…”

Section: Methodsmentioning

confidence: 99%

Multiple novel promoter-architectures revealed by decoding the hidden heterogeneity within the genome

Narlikar

2014

Nucleic Acids Research

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An important question in biology is how different promoter-architectures contribute to the diversity in regulation of transcription initiation. A step forward has been the production of genome-wide maps of transcription start sites (TSSs) using high-throughput sequencing. However, the subsequent step of characterizing promoters and their functions is still largely done on the basis of previously established promoter-elements like the TATA-box in eukaryotes or the -10 box in bacteria. Unfortunately, a majority of promoters and their activities cannot be explained by these few elements. Traditional motif discovery methods that identify novel elements also fail here, because TSS neighborhoods are often highly heterogeneous containing no overrepresented motif. We present a new, organism-independent method that explicitly models this heterogeneity while unraveling different promoter-architectures. For example, in five bacteria, we detect the presence of a pyrimidine preceding the TSS under very specific circumstances. In tuberculosis, we show for the first time that the spacing between the bacterial 10-motif and TSS is utilized by the pathogen for dynamic gene-regulation. In eukaryotes, we identify several new elements that are important for development. Identified promoter-architectures show differential patterns of evolution, chromatin structure and TSS spread, suggesting distinct regulatory functions. This work highlights the importance of characterizing heterogeneity within high-throughput genomic data rather than analyzing average patterns of nucleotide composition.

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“…(17). The sequences corresponding to −45 bp upstream and +5 bp downstream from the TSS were extracted from reference H37Rv sequence.…”

Section: Methodsmentioning

confidence: 99%

Multiple novel promoter-architectures revealed by decoding the hidden heterogeneity within the genome

Narlikar

2014

Nucleic Acids Research

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“…Rose et al also suggest that the C3500149T SNP generates a novel Ϫ10 TANNNT consensus motif, thereby effectively creating a new TSS within the dosR promoter region from which transcription is activated via the housekeeping SigA factor (29,(53)(54)(55). Although this seems a reasonable assumption, it has not been confirmed experimentally.…”

Section: Fig 6 the Dost Defect In Beijing Isolates Has No Impact On Tmentioning

confidence: 99%

Unique Regulation of the DosR Regulon in the Beijing Lineage of Mycobacterium tuberculosis

et al. 2017

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The DosR regulon, a set of 48 genes normally expressed in Mycobacterium tuberculosis under conditions that inhibit aerobic respiration, is controlled via the DosR-DosS/DosT two-component system. While the regulon requires induction in most M. tuberculosis isolates, for members of the Beijing lineage, its expression is uncoupled from the need for signaling. In our attempts to understand the mechanistic basis for this uncoupling in the Beijing background, we previously reported the identification of two synonymous single-nucleotide polymorphisms (SNPs) within the adjacent Rv3134c gene. In the present study, we have interrogated the impact of these SNPs on dosR expression in wild-type strains, as well as a range of dosRdosS-dosT mutants, for both Beijing and non-Beijing M. tuberculosis backgrounds. In this manner, we have unequivocally determined that the C601T dosR promoter SNP is the sole requirement for the dramatic shift in the pattern of DosR regulon expression seen in this globally important lineage. Interestingly, we also show that DosT is completely nonfunctional within these strains. Thus, a complex series of evolutionary steps has led to the present-day Beijing DosR phenotype that, in turn, potentially confers a fitness advantage in the face of some form of host-associated selective pressure.IMPORTANCE Mycobacterium tuberculosis strains of the Beijing lineage have been described as being of enhanced virulence compared to other lineages, and in certain regions, they are associated with the dramatic spread of multidrug-resistant tuberculosis (TB). In terms of trying to understand the functional basis for these broad epidemiological phenomena, it is interesting that, in contrast to the other major lineages, the Beijing strains all constitutively overexpress members of the DosR regulon. Here, we identify the mutational events that led to the evolution of this unique phenotype. In addition, our work highlights the fact that important phenotypic differences exist between distinct M. tuberculosis lineages, with the potential to impact the efficacy of diagnosis, vaccination, and treatment programs.KEYWORDS Tuberculosis, DosR regulon, strain variation, evolution, Mycobacterium tuberculosis D espite being an ancient disease, human tuberculosis (TB) resulting from infection with Mycobacterium tuberculosis still remains a leading cause of death worldwide as a consequence of multiple contributing factors, including drug resistance, HIV coinfection, and inadequate access to high-quality health care (1). Furthermore, recent evidence suggests that the level of genetic diversity that exists among distinct M. tuberculosis isolates was previously underestimated and has the potential to impact pathogenicity, as well as to limit the effectiveness of current diagnostic and therapeutic interventions (2-4).

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“…Several TA loci in M. tuberculosis are induced during heat shock 4 , hypoxia 5,6 , DNA damage 7 , nutrient starvation 8 , macrophage infection 5,9,10 and antibiotic treatment 11,12 . Most recently, RNA-seq analysis of M. tuberculosis cells subjected to starvation revealed that the majority of TA systems, 75%, were upregulated to some degree with 25% upregulated twofold or higher 13 .…”

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confidence: 99%

Growth-regulating Mycobacterium tuberculosis VapC-mt4 toxin is an isoacceptor-specific tRNase

et al. 2015

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Toxin–antitoxin (TA) systems are implicated in the downregulation of bacterial cell growth associated with stress survival and latent tuberculosis infection, yet the activities and intracellular targets of these TA toxins are largely uncharacterized. Here, we use a specialized RNA-seq approach to identify targets of a Mycobacterium tuberculosis VapC TA toxin, VapC-mt4 (also known as VapC4), which have eluded detection using conventional approaches. Distinct from the one other characterized VapC toxin in M. tuberculosis that cuts 23S rRNA at the sarcin–ricin loop, VapC-mt4 selectively targets three of the 45 M. tuberculosis tRNAs (tRNAAla2, tRNASer26 and tRNASer24) for cleavage at, or adjacent to, their anticodons, resulting in the generation of tRNA halves. While tRNA cleavage is sometimes enlisted as a bacterial host defense mechanism, VapC-mt4 instead alters specific tRNAs to inhibit translation and modulate growth. This stress-linked activity of VapC-mt4 mirrors basic features of eukaryotic tRNases that also generate tRNA halves and inhibit translation in response to stress.

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Genome-wide Mapping of Transcriptional Start Sites Defines an Extensive Leaderless Transcriptome in Mycobacterium tuberculosis

Cited by 290 publications

References 64 publications

Multiple novel promoter-architectures revealed by decoding the hidden heterogeneity within the genome

Multiple novel promoter-architectures revealed by decoding the hidden heterogeneity within the genome

Unique Regulation of the DosR Regulon in the Beijing Lineage of Mycobacterium tuberculosis

Growth-regulating Mycobacterium tuberculosis VapC-mt4 toxin is an isoacceptor-specific tRNase

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