Control of Francisella tularensis Virulence at Gene Level: Network of Transcription Factors

Regulation of gene transcription is the initial step in the complex process that controls gene expression within bacteria. Transcriptional control involves the joint effort of RNA polymerases and numerous other regulatory factors. Whether global or local, positive or negative, regulators play an essential role in the bacterial cell. For instance, some regulators specifically modify the transcription of virulence genes, thereby being indispensable to pathogenic bacteria. Here, we provide a comprehensive overview of important transcription factors and DNA-binding proteins described for the virulent bacterium Francisella tularensis, the causative agent of tularemia. This is an unexplored research area, and the poorly described networks of transcription factors merit additional experimental studies to help elucidate the molecular mechanisms of pathogenesis in this bacterium, and how they contribute to disease.

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DksA-dependent regulation of RpoS contributes to Borrelia burgdorferi tick-borne transmission and mammalian infectivity

PLoS Pathogens ◽

10.1371/journal.ppat.1009072 ◽

2021 ◽

Vol 17 (2) ◽

pp. e1009072

Author(s):

William K. Boyle ◽

Crystal L. Richards ◽

Daniel P. Dulebohn ◽

Amanda K. Zalud ◽

Jeff A. Shaw ◽

...

Keyword(s):

Gene Expression ◽

Transcription Factors ◽

Rna Polymerase ◽

Nutrient Limitation ◽

Pathogenic Bacteria ◽

Transcriptional Control ◽

Ixodes Scapularis ◽

Stringent Response ◽

Transcriptional Responses

Throughout its enzootic cycle, the Lyme disease spirochete Borreliella (Borrelia) burgdorferi, senses and responds to changes in its environment using a small repertoire of transcription factors that coordinate the expression of genes required for infection of Ixodes ticks and various mammalian hosts. Among these transcription factors, the DnaK suppressor protein (DksA) plays a pivotal role in regulating gene expression in B. burgdorferi during periods of nutrient limitation and is required for mammalian infectivity. In many pathogenic bacteria, the gene regulatory activity of DksA, along with the alarmone guanosine penta- and tetra-phosphate ((p)ppGpp), coordinate the stringent response to various environmental stresses, including nutrient limitation. In this study, we sought to characterize the role of DksA in regulating the transcriptional activity of RNA polymerase and its role in the regulation of RpoS-dependent gene expression required for B. burgdorferi infectivity. Using in vitro transcription assays, we observed recombinant DksA inhibits RpoD-dependent transcription by B. burgdorferi RNA polymerase independent of ppGpp. Additionally, we determined the pH-inducible expression of RpoS-dependent genes relies on DksA, but this relationship is independent of (p)ppGpp produced by Relbbu. Subsequent transcriptomic and western blot assays indicate DksA regulates the expression of BBD18, a protein previously implicated in the post-transcriptional regulation of RpoS. Moreover, we observed DksA was required for infection of mice following intraperitoneal inoculation or for transmission of B. burgdorferi by Ixodes scapularis nymphs. Together, these data suggest DksA plays a central role in coordinating transcriptional responses in B. burgdorferi required for infectivity through DksA’s interactions with RNA polymerase and post-transcriptional control of RpoS.

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The Transcriptional Control of Lymphatic Vascular Development

Physiology ◽

10.1152/physiol.00053.2010 ◽

2011 ◽

Vol 26 (3) ◽

pp. 146-155 ◽

Cited By ~ 38

Author(s):

Mathias Francois ◽

Natasha L. Harvey ◽

Benjamin M. Hogan

Keyword(s):

Transcription Factors ◽

Cell Fate ◽

Transcriptional Control ◽

Molecular Mechanisms ◽

Developmental Process ◽

Vascular Development ◽

Lymphatic Vessels ◽

Lymphatic Endothelial Cell ◽

Transcriptional Networks ◽

Genetic Manipulations

More than 100 years ago, Florence Sabin suggested that lymphatic vessels develop by sprouting from preexisting blood vessels, but it is only over the past decade that the molecular mechanisms underpinning lymphatic vascular development have begun to be elucidated. Genetic manipulations in mice have identified a transcriptional hub comprised of Prox1, CoupTFII, and Sox18 that is essential for lymphatic endothelial cell fate specification. Recent work has identified a number of additional transcription factors that regulate later stages of lymphatic vessel differentiation and maturation. This review highlights recent advances in our understanding of the transcriptional control of lymphatic vascular development and reflects on efforts to better understand the activities of transcriptional networks during this discrete developmental process. Finally, we highlight the transcription factors associated with human lymphatic vascular disorders, demonstrating the importance of understanding how the activity of these key molecules is regulated, with a view toward the development of innovative therapeutic avenues.

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Widespread targeting of development-related host transcription factors by phytoplasma effectors

10.1101/2020.02.13.946517 ◽

2020 ◽

Author(s):

Miguel Correa Marrero ◽

Sylvain Capdevielle ◽

Weijie Huang ◽

Marco Busscher ◽

Jacqueline Busscher-Lange ◽

...

Keyword(s):

Transcription Factors ◽

Protein Interaction ◽

Protein Interaction Network ◽

Pathogenic Bacteria ◽

Molecular Mechanisms ◽

Interaction Network ◽

Effector Proteins ◽

Insect Vector ◽

Plant Host ◽

Phytoplasma Infection

1AbstractPhytoplasmas are pathogenic bacteria that reprogram plant host development in order to attract their insect vectors to disseminate. Previous studies have characterized a few different phytoplasma effector proteins that supress specific transcription factors. However, these are only a small fraction of the potential effectors used by phytoplasmas, meaning that the molecular mechanisms through which phytoplasmas manipulate their hosts are largely uncharacterized. To obtain further insights into the phytoplasma infection mechanisms, we generated a protein-protein interaction network between a broad set of phytoplasma effectors and a large collection of Arabidopsis thaliana transcription factors and transcriptional regulators. We found widespread, but unique, interactions with host transcription factors by phytoplasma effectors, especially those related to developmental processes. In particular, many unrelated effectors target TCP transcription factors, which play roles in plant development and immunity. Comparison with other host-pathogen protein interaction networks shows that phytoplasma effectors have unusual targets, and indicates that phytoplasmas have evolved a unique and unusual infection strategy. This study provides a rich and solid data source that can be used to predict functional effects of individual effectors and as a guide for detailed studies of individual effectors in the future, as well as insights into the underlying molecular mechanisms of phytoplasma infection.2Significance statementThis work shows that the effectors of phytoplasma, a bacterial plant pathogen, show pervasive interactions with development-related host transcription factors, providing a way to take over plant growth and development in favor of the pathogen and its insect vector. The obtained comprehensive protein interaction network and showcase of the potential biological consequences of a selected effector advance our understanding of phytoplasma-host interactions and provide guidance for further study.

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Progesterone receptor-A isoform interaction with RUNX transcription factors controls chromatin remodelling at promoters during ovulation

10.1101/2021.06.17.448908 ◽

2021 ◽

Author(s):

Thao D Dinh ◽

James Breen ◽

Barbara Nicol ◽

Kirsten M Smith ◽

Matilda Nicholls ◽

...

Keyword(s):

Transcription Factors ◽

Progesterone Receptor ◽

Transcriptional Control ◽

Molecular Mechanisms ◽

Chromatin Accessibility ◽

Proximal Promoter ◽

Physical Interaction ◽

Promoter Regions ◽

Follicle Rupture ◽

Transcriptional Complex

Progesterone receptor (PGR) plays diverse roles in reproductive tissues and thus coordinates mammalian fertility. In the ovary, acutely induced PGR is the key determinant of ovulation through transcriptional control of a unique set of genes that culminates in follicle rupture. However, the molecular mechanisms for PGR specialised function in ovulation is poorly understood. To address this, we assembled a detailed genomic profile of PGR action through combined ATAC-seq, RNA-seq and ChIP-seq analysis in wildtype and isoform-specific PGR null mice. We demonstrated the unique action of PGR-A isoform in the ovary through a transcriptional complex involving physical interaction with RUNX and JUN/FOS transcription factors. The assembly of this unique complex directs targeting of PGR binding to proximal promoter regions and enables chromatin accessibility, leading to ovulatory gene induction. This PGR signalling mechanism is specific to ovulation and provides potential targets for infertility treatments as well as new contraceptives that block ovulation.

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The interaction between MtDELLA-MtGAF1 complex and MtARF3 mediates transcriptional control of MtGA3ox1 to elaborate leaf margin formation in Medicago truncatula

Plant and Cell Physiology ◽

10.1093/pcp/pcaa163 ◽

2021 ◽

Author(s):

Lizhu Wen ◽

Yiming Kong ◽

Hongfeng Wang ◽

Yiteng Xu ◽

Zhichao Lu ◽

...

Keyword(s):

Transcription Factors ◽

Medicago Truncatula ◽

Transcriptional Control ◽

Molecular Mechanisms ◽

Leaf Shape ◽

Critical Role ◽

Competitive Inhibitor ◽

Leaf Margin ◽

Loss Of Function ◽

Model Legume

Abstract The molecular mechanisms underlying diversity of leaf shapes have been of great interest to researchers. Leaf shape depends on the pattern of serrations and the degree of indentation of leaf margins. Multiple transcription factors and hormone signaling are involved in this process. In this study, we characterized the developmental roles of SMALL AND SERRATED LEAF (SSL) by analyzing a recessive mutant in the model legume Medicago truncatula. An ortholog of Arabidopsis thaliana GA3-oxidase 1 (GA3ox1), MtGA3ox1/SSL, is required for GA biosynthesis. Loss of function in MtGA3ox1 results in the small plant and lateral organs. The prominent phenotype of the mtga3ox1 mutant is the more pronounced leaf margin, indicating the critical role of GA level in leaf margin formation. Moreover, 35S: MtDELLA2 ΔDELLAand 35S: MtARF3 transgenic plants display leaves with the deeply wavy margin, which resembles those of mtga3ox1. Further investigations show that the MtGA3ox1 is under the control of MtDELLA1/2/3-MtGAF1 complexes-dependent feedback regulation. Meanwhile, MtARF3 behaves as a competitive inhibitor of MtDELLA2/3-MtGAF1 complexes to repress the expression of MtGA3ox1 indirectly. These findings suggest that GA feedback regulatory circuits play a fundamental role in leaf margin formation, in which the posttranslational interaction between transcription factors functions as an additional feature.

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Transcription factors Mash-1 and Prox-1 delineate early steps in differentiation of neural stem cells in the developing central nervous system

Development ◽

10.1242/dev.126.3.443 ◽

1999 ◽

Vol 126 (3) ◽

pp. 443-456 ◽

Cited By ~ 14

Author(s):

M.a. Torii ◽

F. Matsuzaki ◽

N. Osumi ◽

K. Kaibuchi ◽

S. Nakamura ◽

...

Keyword(s):

Stem Cells ◽

Central Nervous System ◽

Nervous System ◽

Transcription Factors ◽

Cell Differentiation ◽

Early Development ◽

Molecular Mechanisms ◽

Initial Step

Like other tissues and organs in vertebrates, multipotential stem cells serve as the origin of diverse cell types during genesis of the mammalian central nervous system (CNS). During early development, stem cells self-renew and increase their total cell numbers without overt differentiation. At later stages, the cells withdraw from this self-renewal mode, and are fated to differentiate into neurons and glia in a spatially and temporally regulated manner. However, the molecular mechanisms underlying this important step in cell differentiation remain poorly understood. In this study, we present evidence that the expression and function of the neural-specific transcription factors Mash-1 and Prox-1 are involved in this process. In vivo, Mash-1- and Prox-1-expressing cells were defined as a transient proliferating population that was molecularly distinct from self-renewing stem cells. By taking advantage of in vitro culture systems, we showed that induction of Mash-1 and Prox-1 coincided with an initial step of differentiation of stem cells. Furthermore, forced expression of Mash-1 led to the down-regulation of nestin, a marker for undifferentiated neuroepithelial cells, and up-regulation of Prox-1, suggesting that Mash-1 positively regulates cell differentiation. In support of these observations in vitro, we found specific defects in cellular differentiation and loss of expression of Prox-1 in the developing brain of Mash-1 mutant mice in vivo. Thus, we propose that induction of Mash-1 and Prox-1 is one of the critical molecular events that control early development of the CNS.

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Transcriptional Regulation of Metabolism

Physiological Reviews ◽

10.1152/physrev.00025.2005 ◽

2006 ◽

Vol 86 (2) ◽

pp. 465-514 ◽

Cited By ~ 555

Author(s):

Béatrice Desvergne ◽

Liliane Michalik ◽

Walter Wahli

Keyword(s):

Transcriptional Regulation ◽

Transcription Factors ◽

Transcriptional Control ◽

Molecular Mechanisms ◽

Metabolic Diseases ◽

Cholesterol Metabolism ◽

Regulatory Pathways ◽

Glucose And Lipid Metabolism ◽

The Metabolic Syndrome

Our understanding of metabolism is undergoing a dramatic shift. Indeed, the efforts made towards elucidating the mechanisms controlling the major regulatory pathways are now being rewarded. At the molecular level, the crucial role of transcription factors is particularly well-illustrated by the link between alterations of their functions and the occurrence of major metabolic diseases. In addition, the possibility of manipulating the ligand-dependent activity of some of these transcription factors makes them attractive as therapeutic targets. The aim of this review is to summarize recent knowledge on the transcriptional control of metabolic homeostasis. We first review data on the transcriptional regulation of the intermediary metabolism, i.e., glucose, amino acid, lipid, and cholesterol metabolism. Then, we analyze how transcription factors integrate signals from various pathways to ensure homeostasis. One example of this coordination is the daily adaptation to the circadian fasting and feeding rhythm. This section also discusses the dysregulations causing the metabolic syndrome, which reveals the intricate nature of glucose and lipid metabolism and the role of the transcription factor PPARγ in orchestrating this association. Finally, we discuss the molecular mechanisms underlying metabolic regulations, which provide new opportunities for treating complex metabolic disorders.

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Emerging cellular and molecular mechanisms underlying anticancer indications of chrysin

Cancer Cell International ◽

10.1186/s12935-021-01906-y ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Marjan Talebi ◽

Mohsen Talebi ◽

Tahereh Farkhondeh ◽

Jesus Simal-Gandara ◽

Dalia M. Kopustinskiene ◽

...

Keyword(s):

Blood Cells ◽

Molecular Mechanisms ◽

Web Of Science ◽

Experimental Studies ◽

Protective Effects ◽

Pharmacological Activities ◽

Current Review ◽

Mesh Terms ◽

Online Databases ◽

Anti Cancer

AbstractChrysin has been shown to exert several beneficial pharmacological activities. Chrysin has anti-cancer, anti-viral, anti-diabetic, neuroprotective, cardioprotective, hepatoprotective, and renoprotective as well as gastrointestinal, respiratory, reproductive, ocular, and skin protective effects through modulating signaling pathway involved in apoptosis, oxidative stress, and inflammation. In the current review, we discussed the emerging cellular and molecular mechanisms underlying therapeutic indications of chrysin in various cancers. Online databases comprising Scopus, PubMed, Embase, ProQuest, Science Direct, Web of Science, and the search engine Google Scholar were searched for available and eligible research articles. The search was conducted by using MeSH terms and keywords in title, abstract, and keywords. In conclusion, experimental studies indicated that chrysin could ameliorate cancers of the breast, gastrointestinal tract, liver and hepatocytes, bladder, male and female reproductive systems, choroid, respiratory tract, thyroid, skin, eye, brain, blood cells, leukemia, osteoblast, and lymph. However, more studies are needed to enhance the bioavailability of chrysin and evaluate this agent in clinical trial studies. Graphic abstract

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Therapies for the Treatment of Cardiovascular Disease Associated with Type 2 Diabetes and Dyslipidemia

International Journal of Molecular Sciences ◽

10.3390/ijms22020660 ◽

2021 ◽

Vol 22 (2) ◽

pp. 660

Author(s):

María Aguilar-Ballester ◽

Gema Hurtado-Genovés ◽

Alida Taberner-Cortés ◽

Andrea Herrero-Cervera ◽

Sergio Martínez-Hervás ◽

...

Keyword(s):

Type 2 Diabetes ◽

Cardiovascular Disease ◽

Molecular Mechanisms ◽

Foam Cell ◽

Leukocyte Adhesion ◽

Experimental Studies ◽

Lipid Lowering ◽

Foam Cell Formation ◽

Relevant Parameter

Cardiovascular disease (CVD) is the leading cause of death worldwide and is the clinical manifestation of the atherosclerosis. Elevated LDL-cholesterol levels are the first line of therapy but the increasing prevalence in type 2 diabetes mellitus (T2DM) has positioned the cardiometabolic risk as the most relevant parameter for treatment. Therefore, the control of this risk, characterized by dyslipidemia, hypertension, obesity, and insulin resistance, has become a major goal in many experimental and clinical studies in the context of CVD. In the present review, we summarized experimental studies and clinical trials of recent anti-diabetic and lipid-lowering therapies targeted to reduce CVD. Specifically, incretin-based therapies, sodium-glucose co-transporter 2 inhibitors, and proprotein convertase subtilisin kexin 9 inactivating therapies are described. Moreover, the novel molecular mechanisms explaining the CVD protection of the drugs reviewed here indicate major effects on vascular cells, inflammatory cells, and cardiomyocytes, beyond their expected anti-diabetic and lipid-lowering control. The revealed key mechanism is a prevention of acute cardiovascular events by restraining atherosclerosis at early stages, with decreased leukocyte adhesion, recruitment, and foam cell formation, and increased plaque stability and diminished necrotic core in advanced plaques. These emergent cardiometabolic therapies have a promising future to reduce CVD burden.

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MGA2 and SPT23 Are Modifiers of Transcriptional Silencing in Yeast

Genetics ◽

10.1093/genetics/156.3.933 ◽

2000 ◽

Vol 156 (3) ◽

pp. 933-941 ◽

Cited By ~ 1

Author(s):

Mary Lou Dula ◽

Scott G Holmes

Keyword(s):

Transcription Factors ◽

Chromatin Structure ◽

Transcriptional Control ◽

Transcriptional Silencing ◽

Sir Proteins

Abstract Transcriptional silencing at the HM loci and telomeres in yeast depends on several trans-acting factors, including Rap1p and the Sir proteins. The SUM1-1 mutation was identified by its ability to restore silencing to strains deficient in one or more of these trans-acting factors. The mechanism by which SUM1-1 bypasses the requirement for silencing proteins is not known. We identified four loci that when reduced in dosage in diploid strains increase the ability of SUM1-1 strains to suppress silencing defects. Two of the genes responsible for this effect were found to be MGA2 and SPT23. Mga2p and Spt23p were previously identified as functionally related transcription factors that influence chromatin structure. We find that deletion of MGA2 or SPT23 also increases the efficiency of silencing in haploid SUM1-1 strains. These results suggest that Mga2p and Spt23p are antagonists of silencing. Consistent with this proposal we find that deletion of MGA2 or SPT23 also suppresses the silencing defects caused by deletion of the SIR1 gene or by mutations in the HMR silencer sequences. However, we find that Mga2p and Spt23p can positively affect silencing in other contexts; deletion of either MGA2 or SPT23 decreases mating in strains bearing mutations in the HML-E silencer. Mga2p and Spt23p appear to be a novel class of factors that influence disparate pathways of transcriptional control by chromatin.

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