scholarly journals Progression of recent Mycobacterium tuberculosis exposure to active tuberculosis is a highly heritable complex trait driven by 3q23 in Peruvians

2018 ◽  
Author(s):  
Yang Luo ◽  
Sara Suliman ◽  
Samira Asgari ◽  
Tiffany Amariuta ◽  
Roger Calderon ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Target Genes ◽  
Complex Trait ◽  
Active Tuberculosis ◽  
Functional Variants ◽  
Genetic Heritability ◽  
Genome Wide ◽  
Novel Association ◽  
Host Genetic

AbstractAmong 1.8 billion people worldwide infected with Mycobacterium tuberculosis, 5-15% are expected to develop active tuberculosis (TB). Approximately half of these will progress to active TB within the first 18 months after infection, presumably because they fail to mount the initial immune response that contains the local bacterial spread. The other half will reactivate their latent infection later in life, likely triggered by a loss of immune competence due to factors such as HIV-associated immunosuppression or ageing. This natural history suggests that undiscovered host genetic factors may control early progression to active TB. Here, we report results from a large genome-wide genetic study of early TB progression. We genotyped a total of 4,002 active TB cases and their household contacts in Peru and quantified genetic heritability of early TB progression to be 21.2% under the liability scale. Compared to the reported of genome-wide TB susceptibility (15.5%), this result indicates early TB progression has a stronger genetic basis than population-wide TB susceptibility. We identified a novel association between early TB progression and variants located in an enhancer region on chromosome 3q23 (rs73226617, OR=1.19; P < 5×10−8). We used in silico and in vitro analyses to identify likely functional variants and target genes, highlighting new candidate mechanisms of host response in early TB progression.

scholarly journals Genome-Wide Binding Analyses of HOXB1 Revealed a Novel DNA Binding Motif Associated with Gene Repression

2021 ◽  
Vol 9 (1) ◽  
pp. 6
Author(s):  
Narendra Pratap Singh ◽  
Bony De Kumar ◽  
Ariel Paulson ◽  
Mark E. Parrish ◽  
Carrie Scott ◽  
...  
Keyword(s):  
Dna Binding ◽  
Target Genes ◽  
Embryonic Stem ◽  
Binding Motif ◽  
Binding Assays ◽  
Histone Marks ◽  
Genome Wide ◽  
Hox Cofactors

Knowledge of the diverse DNA binding specificities of transcription factors is important for understanding their specific regulatory functions in animal development and evolution. We have examined the genome-wide binding properties of the mouse HOXB1 protein in embryonic stem cells differentiated into neural fates. Unexpectedly, only a small number of HOXB1 bound regions (7%) correlate with binding of the known HOX cofactors PBX and MEIS. In contrast, 22% of the HOXB1 binding peaks display co-occupancy with the transcriptional repressor REST. Analyses revealed that co-binding of HOXB1 with PBX correlates with active histone marks and high levels of expression, while co-occupancy with REST correlates with repressive histone marks and repression of the target genes. Analysis of HOXB1 bound regions uncovered enrichment of a novel 15 base pair HOXB1 binding motif HB1RE (HOXB1 response element). In vitro template binding assays showed that HOXB1, PBX1, and MEIS can bind to this motif. In vivo, this motif is sufficient for direct expression of a reporter gene and over-expression of HOXB1 selectively represses this activity. Our analyses suggest that HOXB1 has evolved an association with REST in gene regulation and the novel HB1RE motif contributes to HOXB1 function in part through a repressive role in gene expression.

scholarly journals De Novo Emergence of Genetically Resistant Mutants of Mycobacterium tuberculosis from the Persistence Phase Cells Formed against Antituberculosis Drugs In Vitro

2016 ◽  
Vol 61 (2) ◽  
Author(s):  
Jees Sebastian ◽  
Sharmada Swaminath ◽  
Rashmi Ravindran Nair ◽  
Kishor Jakkala ◽  
Atul Pradhan ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Hydroxyl Radical ◽  
Prolonged Exposure ◽  
De Novo ◽  
Random Mutagenesis ◽  
Content Type ◽  
Genome Wide ◽  
Resistant Mutants ◽  
Phase Population

ABSTRACT Bacterial persisters are a subpopulation of cells that can tolerate lethal concentrations of antibiotics. However, the possibility of the emergence of genetically resistant mutants from antibiotic persister cell populations, upon continued exposure to lethal concentrations of antibiotics, remained unexplored. In the present study, we found that Mycobacterium tuberculosis cells exposed continuously to lethal concentrations of rifampin (RIF) or moxifloxacin (MXF) for prolonged durations showed killing, RIF/MXF persistence, and regrowth phases. RIF-resistant or MXF-resistant mutants carrying clinically relevant mutations in the rpoB or gyrA gene, respectively, were found to emerge at high frequency from the RIF persistence phase population. A Luria-Delbruck fluctuation experiment using RIF-exposed M. tuberculosis cells showed that the rpoB mutants were not preexistent in the population but were formed de novo from the RIF persistence phase population. The RIF persistence phase M. tuberculosis cells carried elevated levels of hydroxyl radical that inflicted extensive genome-wide mutations, generating RIF-resistant mutants. Consistent with the elevated levels of hydroxyl radical-mediated genome-wide random mutagenesis, MXF-resistant M. tuberculosis gyrA de novo mutants could be selected from the RIF persistence phase cells. Thus, unlike previous studies, which showed emergence of genetically resistant mutants upon exposure of bacteria for short durations to sublethal concentrations of antibiotics, our study demonstrates that continuous prolonged exposure of M. tuberculosis cells to lethal concentrations of an antibiotic generates antibiotic persistence phase cells that form a reservoir for the generation of genetically resistant mutants to the same antibiotic or another antibiotic. These findings may have clinical significance in the emergence of drug-resistant tubercle bacilli.

scholarly journals A vitamin B 12 transporter in Mycobacterium tuberculosis

Open Biology ◽  
2013 ◽  
Vol 3 (2) ◽  
pp. 120175 ◽  
Author(s):  
Krishnamoorthy Gopinath ◽  
Česlovas Venclovas ◽  
Thomas R. Ioerger ◽  
James C. Sacchettini ◽  
John D. McKinney ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Type System ◽  
Mycobacterial Infection ◽  
Vitamin B ◽  
Abc Protein ◽  
Genome Wide ◽  
Host Infection ◽  
Obligate Pathogen

Vitamin B 12 -dependent enzymes function in core biochemical pathways in Mycobacterium tuberculosis , an obligate pathogen whose metabolism in vivo is poorly understood. Although M. tuberculosis can access vitamin B 12 in vitro , it is uncertain whether the organism is able to scavenge B 12 during host infection. This question is crucial to predictions of metabolic function, but its resolution is complicated by the absence in the M. tuberculosis genome of a direct homologue of BtuFCD, the only bacterial B 12 transport system described to date. We applied genome-wide transposon mutagenesis to identify M. tuberculosis mutants defective in their ability to use exogenous B 12 . A small proportion of these mapped to Rv1314c , identifying the putative PduO-type ATP : co(I)rrinoid adenosyltransferase as essential for B 12 assimilation. Most notably, however, insertions in Rv1819c dominated the mutant pool, revealing an unexpected function in B 12 acquisition for an ATP-binding cassette (ABC)-type protein previously investigated as the mycobacterial BacA homologue. Moreover, targeted deletion of Rv1819c eliminated the ability of M. tuberculosis to transport B 12 and related corrinoids in vitro . Our results establish an alternative to the canonical BtuCD-type system for B 12 uptake in M. tuberculosis , and elucidate a role in B 12 metabolism for an ABC protein implicated in chronic mycobacterial infection.

scholarly journals The COMPASS-like complex modulates fungal development and pathogenesis by regulating H3K4me3-mediated targeted gene expression in Magnaporthe oryzae

2020 ◽  
Author(s):  
Sida Zhou ◽  
Wanyu Sun ◽  
Xinyu Zhao ◽  
Yang Xu ◽  
Mengyu Zhang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Magnaporthe Oryzae ◽  
Target Genes ◽  
H3k4 Methylation ◽  
Affinity Tag ◽  
Fungal Development ◽  
Pathogenic Genes ◽  
Genome Wide ◽  
Highly Correlated

ABSTRACTHistone H3K4 methylation is catalysed by the multi-protein complex known as the Set1/COMPASS or MLL/COMPASS-like complex, an element that is highly evolutionarily conserved from yeast to humans. However, the components and mechanisms by which the COMPASS-like complex targets the H3K4 methylation of plant pathogenic genes in fungi remain elusive. Here we present a comprehensive analysis combining biochemical, molecular, and genome-wide approaches to characterize the roles of the COMPASS-like family in Magnaporthe oryzae, a model plant fungal pathogen. We purified and identified six conserved subunits of COMPASS from the rice blast fungus M. oryzae, i.e., MoBre2 (Cps60/ASH2L), MoSpp1 (Cps40/Cfp1), MoSwd2 (Cps35), MoSdc1 (Cps25/DPY30), MoSet1 (MLL/ALL) and MoRbBP5 (Cps50), using an affinity tag on MoBre2. We determined the SPRY domain of MoBre2 can recognize directly with DPY30 domain of MoSdc1 in vitro. Furthermore, we found that deletion of the genes encoding COMPASS subunits of MoBre2, MoSpp1 and MoSwd2 caused similar defects regarding invasive hyphal development and pathogenicity. Genome-wide profiling of H3K4me3 revealed that the it has remarkable co-occupancy at the TSS regions of target genes. Significantly, these target genes are often involved in spore germination and pathogenesis. Decreased gene expression caused by the deletion of MoBre2, MoSwd2 or MoSpp1 gene was highly correlated with decrease in H3K4me3. Taken together, these results suggest that MoBre2, MoSpp1, and MoSwd2 function as a whole COMPASS complex, contributing to fungal development and pathogenesis by regulating H3K4me3-targeted genes in M. oryzae.

scholarly journals Hybrid allele-specific ChIP-Seq analysis links variation in transcription factor binding to traits in maize

2021 ◽  
Author(s):  
Thomas Hartwig ◽  
Michael Banf ◽  
Gisele Prietsch ◽  
Julia Engelhorn ◽  
Jinliang Yang ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Target Genes ◽  
Phenotypic Diversity ◽  
Association Studies ◽  
Chromatin Accessibility ◽  
Genome Wide Association Studies ◽  
Functional Variants ◽  
Genome Wide ◽  
Allele Specific ◽  
Hybrid Allele

Abstract Variation in transcriptional regulation is a major cause of phenotypic diversity. Genome-wide association studies (GWAS) have shown that most functional variants reside in non-coding regions, where they potentially affect transcription factor (TF) binding and chromatin accessibility to alter gene expression. Pinpointing such regulatory variations, however, remains challenging. Here, we developed a hybrid allele-specific chromatin binding sequencing (HASCh-seq) approach and identified variations in target binding of the brassinosteroid (BR) responsive transcription factor ZmBZR1 in maize. Chromatin immunoprecipitation followed by sequencing (ChIP-seq) in B73xMo17 F1s identified thousands of target genes of ZmBZR1. Allele-specific ZmBZR1 binding (ASB) was observed for about 14.3% of target genes. It correlated with over 550 loci containing sequence variation in BZR1-binding motifs and over 340 loci with haplotype-specific DNA methylation, linking genetic and epigenetic variations to ZmBZR1 occupancy. Comparison with GWAS data linked hundreds of ASB loci to important yield, growth, and disease-related traits. Our study provides a robust method for analyzing genome-wide variations of transcription factor occupancy and identified genetic and epigenetic variations of the BR response transcription network in maize.

Transcriptional enhancers: from prediction to functional assessment on a genome-wide scale

Genome ◽  
2020 ◽  
pp. 1-23
Author(s):  
Ian C. Tobias ◽  
Luis E. Abatti ◽  
Sakthi D. Moorthy ◽  
Shanelle Mullany ◽  
Tiegh Taylor ◽  
...  
Keyword(s):  
High Throughput Screening ◽  
Target Genes ◽  
Regulatory Sequences ◽  
Enhancer Activity ◽  
Reading Frame ◽  
Enhancer Prediction ◽  
Genome Wide ◽  
A Genome ◽  
Enhancer Function

Enhancers are cis-regulatory sequences located distally to target genes. These sequences consolidate developmental and environmental cues to coordinate gene expression in a tissue-specific manner. Enhancer function and tissue specificity depend on the expressed set of transcription factors, which recognize binding sites and recruit cofactors that regulate local chromatin organization and gene transcription. Unlike other genomic elements, enhancers are challenging to identify because they function independently of orientation, are often distant from their promoters, have poorly defined boundaries, and display no reading frame. In addition, there are no defined genetic or epigenetic features that are unambiguously associated with enhancer activity. Over recent years there have been developments in both empirical assays and computational methods for enhancer prediction. We review genome-wide tools, CRISPR advancements, and high-throughput screening approaches that have improved our ability to both observe and manipulate enhancers in vitro at the level of primary genetic sequences, chromatin states, and spatial interactions. We also highlight contemporary animal models and their importance to enhancer validation. Together, these experimental systems and techniques complement one another and broaden our understanding of enhancer function in development, evolution, and disease.

scholarly journals Direct Targets of CodY in Staphylococcus aureus

2010 ◽  
Vol 192 (11) ◽  
pp. 2861-2877 ◽  
Author(s):  
Charlotte D. Majerczyk ◽  
Paul M. Dunman ◽  
Thanh T. Luong ◽  
Chia Y. Lee ◽  
Marat R. Sadykov ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Target Genes ◽  
Adaptive Responses ◽  
Dnase I Footprinting ◽  
Genome Wide ◽  
Branched Chain ◽  
Intracellular Metabolite Pools ◽  
Transport Of Macromolecules ◽  
Direct Regulator

ABSTRACT More than 200 direct CodY target genes in Staphylococcus aureus were identified by genome-wide analysis of in vitro DNA binding. This analysis, which was confirmed for some genes by DNase I footprinting assays, revealed that CodY is a direct regulator of numerous transcription units associated with amino acid biosynthesis, transport of macromolecules, and virulence. The virulence genes regulated by CodY fell into three groups. One group was dependent on the Agr system for its expression; these genes were indirectly regulated by CodY through its repression of the agr locus. A second group was regulated directly by CodY. The third group, which includes genes for alpha-toxin and capsule synthesis, was regulated by CodY in two ways, i.e., by direct repression and by repression of the agr locus. Since S. aureus CodY was activated in vitro by the branched chain amino acids and GTP, CodY appears to link changes in intracellular metabolite pools with the induction of numerous adaptive responses, including virulence.

scholarly journals The Use of Interferon Gamma Release Assays in the Diagnosis of Active Tuberculosis

2012 ◽  
Vol 2012 ◽  
pp. 1-4 ◽  
Author(s):  
Silvan M. Vesenbeckh ◽  
Nicolas Schönfeld ◽  
Harald Mauch ◽  
Thorsten Bergmann ◽  
Sonja Wagner ◽  
...  
Keyword(s):  
Differential Diagnosis ◽  
Mycobacterium Tuberculosis ◽  
Interferon Gamma ◽  
Case Series ◽  
Latent Tuberculosis ◽  
Active Tuberculosis ◽  
Interferon Gamma Release Assays ◽  
Low Incidence ◽  
Low Prevalence

Interferon gamma release assays (IGRAs) arein vitroimmunologic diagnostic tests used to identifyMycobacterium tuberculosisinfection. They cannot differentiate between latent and active infections. The cutoff suggested by the manufacturer is 0.35 IU/mL for latent tuberculosis. As IGRA tests were recently approved for the differential diagnosis of active tuberculosis, we assessed the diagnostic accuracy of the latest generation IGRA for detection of active tuberculosis in a low-incidence area in Germany. Our consecutive case series includes 61 HIV negative,Mycobacterium tuberculosisculture positive patients, as well as 234 control patients. The retrospective analysis was performed over a period of two years. In 11/61 patients with active tuberculosis (18.0%) the test result was <0.35 IU/mL, resulting in a sensitivity of 0.82. We recommend establishing a new cut-off value for the differential diagnosis of active tuberculosis assessed by prospective clinical studies and in various regions with high and low prevalence of tuberculosis.

scholarly journals Type I interferon signaling mediates Mycobacterium tuberculosis–induced macrophage death

2020 ◽  
Vol 218 (2) ◽  
Author(s):  
Li Zhang ◽  
Xiuju Jiang ◽  
Daniel Pfau ◽  
Yan Ling ◽  
Carl F. Nathan
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Critical Role ◽  
Type I ◽  
Type I Ifn ◽  
Paracrine Signaling ◽  
Type I Ifns ◽  
Genome Wide ◽  
Mouse Macrophages ◽  
Definition Of

Macrophages help defend the host against Mycobacterium tuberculosis (Mtb), the major cause of tuberculosis (TB). Once phagocytized, Mtb resists killing by macrophages, replicates inside them, and leads to their death, releasing Mtb that can infect other cells. We found that the death of Mtb-infected mouse macrophages in vitro does not appear to proceed by a currently known pathway. Through genome-wide CRISPR-Cas9 screening, we identified a critical role for autocrine or paracrine signaling by macrophage-derived type I IFNs in the death of Mtb-infected macrophages in vitro, and blockade of type I IFN signaling augmented the effect of rifampin, a first-line TB drug, in Mtb-infected mice. Further definition of the pathway of type I IFN–mediated macrophage death may allow for host-directed therapy of TB that is more selective than systemic blockade of type I IFN signaling.

scholarly journals ROS/RNS balancing, aerobic fermentation regulation and cell cycle control a complex early trait ('CoV-MAC-TED') for combating SARS-CoV-2-induced cell reprogramming

2021 ◽  
Author(s):  
Jose Helio Costa ◽  
Gunasekharan Mohanapriya ◽  
Bharadwaj Revuru ◽  
Carlos Noceda ◽  
Karine Leitao Lima Thiers ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Target Genes ◽  
De Novo ◽  
Cell Cycle Control ◽  
Redox Homeostasis ◽  
Complex Trait ◽  
Transcript Level ◽  
Aerobic Fermentation ◽  
General Observation

In a perspective entitled From plant survival under severe stress to anti-viral human defense we raised and justified the hypothesis that transcript level profiles of justified target genes established from in vitro somatic embryogenesis (SE) induction in plants as a reference compared to virus-induced profiles can identify differential virus signatures that link to harmful reprogramming. A standard profile of selected genes named ReprogVirus was proposed for in vitro-scanning of early virus-induced reprogramming in critical primary infected cells/tissues as target trait. For data collection, the ReprogVirus platform was initiated. This initiative aims to identify in a common effort across scientific boundaries critical virus footprints from diverse virus origins and variants as a basis for anti-viral strategy design. This approach is open for validation and extension. In the present study, we initiated validation by experimental transcriptome data available in public domain combined with advancing plant wet lab research. We compared plant-adapted transcriptomes according to RegroVirus complemented by alternative oxidase (AOX) genes during de novo programming under SE-inducing conditions with in vitro corona virus-induced transcriptome profiles. This approach enabled identifying a major complex trait for early de novo programming during SARS-CoV-2 infection, called CoV-MAC-TED. It consists of unbalanced ROS/RNS levels, which are connected to increased aerobic fermentation that links to alpha-tubulin-based cell restructuration and progression of cell cycle. We conclude that anti-viral/anti-SARS-CoV-2 strategies need to rigorously target CoV-MAC-TED in primary infected nose and mouth cells through prophylactic and very early therapeutic strategies. We also discuss potential strategies in the view of the beneficial role of AOX for resilient behavior in plants. Furthermore, following the general observation that ROS/RNS equilibration/redox homeostasis is of utmost importance at the very beginning of viral infection, we highlight that de-stressing disease and social handling should be seen as essential part of anti-viral/anti-SARS-CoV-2 strategies.

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