Browse
Submit Data
Databases
API
Help

Dataset Information

21 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

"Reading" a new chapter in protozoan parasite transcriptional regulation.

ABSTRACT: Protozoan parasites continue to cause a significant health and economic burden worldwide. As infectious organisms, they pose unique and difficult challenges due to a level of conservation of critical eukaryotic cellular pathways with their hosts. Gene regulation has been pinpointed as an essential pathway with enough divergence to warrant investigation into therapeutically targeting. Examination of human parasites such as Plasmodium falciparum, Toxoplasma gondii, and kinetoplastids have revealed that epigenetic mechanisms play a key role in their gene regulation. The enzymes involved in adding and removing epigenetic posttranslational modifications (PTMs) have historically been the focus of study. However, the reader proteins that recognize and bind PTMs, initiating recruitment of chromatin-modifying and transcription complexes, are now being realized for their critical role in regulation and their potential as drug targets. In this review, we highlight the current knowledge on epigenetic reader proteins in model parasitic protozoa, focusing on the histone acyl- and methyl-reading domains. With this knowledge base, we compare differences between medically relevant parasites, discuss conceivable functions of these understudied proteins, indicate gaps in knowledge, and provide current progress in drug development.

SUBMITTER: Fleck K

PROVIDER: S-EPMC8638923 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Transcriptional regulation of two stage-specifically expressed genes in the protozoan parasite Toxoplasma gondii.

Project description:The protozoan parasite Toxoplasma gondii differentially expresses two distinct enolase isoenzymes known as ENO1 and ENO2, respectively. To understand differential gene expression during tachyzoite to bradyzoite conversion, we have characterized the two T.gondii enolase promoters. No homology could be found between these sequences and no TATA or CCAAT boxes were evident. The differential activation of the ENO1 and ENO2 promoters during tachyzoite to bradyzoite differentiation was investigated by deletion analysis of 5'-flanking regions fused to the chloramphenicol acetyltransferase reporter followed by transient transfection. Our data indicate that in proliferating tachyzoites, the repression of ENO1 involves a negative distal regulatory region (nucleotides -1245 to -625) in the promoter whereas a proximal regulatory region in the ENO2 promoter directs expression at a low level. In contrast, the promoter activity of ENO1 is highly induced following the conversion of tachyzoites into resting bradyzoites. The ENO2 promoter analysis in bradyzoites showed that there are two upstream repression sites (nucleotides -1929 to -1067 and -456 to -222). Furthermore, electrophoresis mobility shift assays demonstrated the presence of DNA-binding proteins in tachyzoite and bradyzoite nuclear lysates that bound to stress response elements (STRE), heat shock-like elements (HSE) and other cis-regulatory elements in the upstream regulatory regions of ENO1 and ENO2. Mutation of the consensus AGGGG sequence, completely abolished protein binding to an oligonucleotide containing this element. This study defines the first characterization of cis-regulatory elements and putative transcription factors involved in gene regulation of the important pathogen T.gondii.

| S-EPMC1903550 | biostudies-literature

Regulation of Translation in the Protozoan Parasite Leishmania.

Project description:Leishmaniasis represents a serious health problem worldwide and drug resistance is a growing concern. Leishmania parasites use unusual mechanisms to control their gene expression. In contrast to many other species, they do not have transcriptional regulation. The lack of transcriptional control is mainly compensated by post-transcriptional mechanisms, including tight translational control and regulation of mRNA stability/translatability by RNA-binding proteins. Modulation of translation plays a major role in parasite survival and adaptation to dramatically different environments during change of host; however, our knowledge of fine molecular mechanisms of translation in Leishmania remains limited. Here, we review the current progress in our understanding of how changes in the translational machinery promote parasite differentiation during transmission from a sand fly to a mammalian host, and discuss how translational reprogramming can contribute to the development of drug resistance.

| S-EPMC7215931 | biostudies-literature

Multifarious transcriptional regulation of adhesion protein gene ap65-1 by a novel Myb1 protein in the protozoan parasite Trichomonas vaginalis.

Project description:The transcription efficiency of an adhesion protein gene, ap65-1, in Trichomonas vaginalis varies with changes in the iron supply and with the growth stage. In the present study, two Myb recognition elements, MRE-1/MRE-2r and MRE-2f, were found to play antagonistic roles in regulating the iron-inducible activity of an ap65-1 reporter gene. Intriguingly, either of these elements was shown to be sufficient to repress basal activity, but together they were also shown to activate growth-related activity of the reporter gene in iron-depleted cells. A myb1 gene which encodes a 24-kDa protein containing a Myb-like R2R3 DNA binding domain was identified from Southwestern screening of MRE-2f-binding proteins. The Myb1 protein was detected as a major 35-kDa protein which exhibited variations in nuclear concentration with changes in the iron supply. A recombinant Myb1 protein was shown to differentially interact with MRE-1/MRE-2r and MRE-2f in vitro. Overexpression of hemagglutinin-tagged Myb1 in T. vaginalis resulted in repression or activation of ap65-1 transcription in iron-depleted cells at an early and a late stage of cell growth, respectively, while iron-inducible ap65-1 transcription was constitutively repressed. The hemagglutinin-tagged Myb1 protein was found to constantly occupy the chromosomal ap65-1 promoter at a proximal site, but it also selected two more distal sites only at the late growth stage. Together, these observations suggest that Myb1 critically regulates multifarious ap65-1 transcription, possibly via differential selection of multiple promoter sites upon environmental changes.

| S-EPMC1405892 | biostudies-literature

CircRNA-Mediated Regulation of Angiogenesis: A New Chapter in Cancer Biology.

Project description:Angiogenesis is necessary for carcinoma progression and is regulated by a variety of pro- and anti-angiogenesis factors. CircRNAs are RNA molecules that do not have a 5'-cap or a 3'-polyA tail and are involved in a variety of biological functions. While circRNA-mediated regulation of tumor angiogenesis has received much attention, the detailed biological regulatory mechanism remains unclear. In this review, we investigated circRNAs in tumor angiogenesis from multiple perspectives, including its upstream and downstream factors. We believe that circRNAs have natural advantages and great potential for the diagnosis and treatment of tumors, which deserves further exploration.

| S-EPMC7988083 | biostudies-literature

Epigenome mapping highlights chromatin-mediated gene regulation in the protozoan parasite Trichomonas vaginalis.

Project description:Trichomonas vaginalis is an extracellular flagellated protozoan parasite that causes trichomoniasis, one of the most common non-viral sexually transmitted diseases. To survive and to maintain infection, T. vaginalis adapts to a hostile host environment by regulating gene expression. However, the mechanisms of transcriptional regulation are poorly understood for this parasite. Histone modification has a marked effect on chromatin structure and directs the recruitment of transcriptional machinery, thereby regulating essential cellular processes. In this study, we aimed to outline modes of chromatin-mediated gene regulation in T. vaginalis. Inhibition of histone deacetylase (HDAC) alters global transcriptional responses and induces hyperacetylation of histones and hypermethylation of H3K4. Analysis of the genome of T. vaginalis revealed that a number of enzymes regulate histone modification, suggesting that epigenetic mechanisms are important to controlling gene expression in this organism. Additionally, we describe the genome-wide localization of two histone H3 modifications (H3K4me3 and H3K27Ac), which we found to be positively associated with active gene expression in both steady and dynamic transcriptional states. These results provide the first direct evidence that histone modifications play an essential role in transcriptional regulation of T. vaginalis, and may help guide future epigenetic research into therapeutic intervention strategies against this parasite.

| S-EPMC5366954 | biostudies-literature

The unfolded protein response in the protozoan parasite Toxoplasma gondii features translational and transcriptional control.

Project description:The unfolded protein response (UPR) is an important regulatory network that responds to perturbations in protein homeostasis in the endoplasmic reticulum (ER). In mammalian cells, the UPR features translational and transcriptional mechanisms of gene expression aimed at restoring proteostatic control. A central feature of the UPR is phosphorylation of the ? subunit of eukaryotic initiation factor-2 (eIF2) by PERK (EIF2AK3/PEK), which reduces the influx of nascent proteins into the ER by lowering global protein synthesis, coincident with preferential translation of key transcription activators of genes that function to expand the processing capacity of this secretory organelle. Upon ER stress, the apicomplexan parasite Toxoplasma gondii is known to induce phosphorylation of Toxoplasma eIF2? and lower translation initiation. To characterize the nature of the ensuing UPR in this parasite, we carried out microarray analyses to measure the changes in the transcriptome and in translational control during ER stress. We determined that a collection of transcripts linked with the secretory process are induced in response to ER stress, supporting the idea that a transcriptional induction phase of the UPR occurs in Toxoplasma. Furthermore, we determined that about 500 gene transcripts showed enhanced association with translating ribosomes during ER stress. Many of these target genes are suggested to be involved in gene expression, including JmjC5, which continues to be actively translated during ER stress. This study indicates that Toxoplasma triggers a UPR during ER stress that features both translational and transcriptional regulatory mechanisms, which is likely to be important for parasite invasion and development.

| S-EPMC3697469 | biostudies-literature

Differentiation mutants in the protozoan parasite Toxoplasma gondii.

Project description:Two forms of the protozoan parasite Toxoplasma gondii are associated with intermediate hosts such as humans: rapidly growing tachyzoites are responsible for acute illness, whereas slowly dividing encysted bradyzoites can remain latent within the tissues for the life of the host. In order to identify genetic factors associated with parasite differentiation, we have used a strong bradyzoite-specific promoter (identified by promoter trapping) to drive the expression of T. gondii hypoxanthine-xanthine-guanine phosphoribosyltransferase (HXGPRT) in stable transgenic parasites, providing a stage-specific positive/negative selectable marker. Insertional mutagenesis has been carried out on this parental line, followed by bradyzoite induction in vitro and selection in 6-thioxanthine to identify misregulation mutants. Two different mutants fail to induce the HXGPRT gene efficiently during bradyzoite differentiation. These mutants are also defective in other aspects of differentiation: they replicate well under bradyzoite growth conditions, lysing the host cell monolayer as effectively as tachyzoites. Expression of the major bradyzoite antigen BAG1 is reduced, and staining with Dolichos biflorus lectin shows reduced cyst wall formation. Microarray hybridizations show that these mutants behave more like tachyzoites at a global level, even under bradyzoite differentiation conditions. Set of arrays organized by shared biological context, such as organism, tumors types, processes, etc. Keywords: Logical Set

2005-08-13 | GSE3119 | GEO

Differentiation mutants in the protozoan parasite Toxoplasma gondii.

2005-08-13 | E-GEOD-3119 | biostudies-arrayexpress

IMP dehydrogenase from the protozoan parasite Toxoplasma gondii.

Project description:The opportunistic apicomplexan parasite Toxoplasma gondii damages fetuses in utero and threatens immunocompromised individuals. The toxicity associated with standard antitoxoplasmal therapies, which target the folate pathway, underscores the importance of examining alternative pharmacological strategies. Parasitic protozoa cannot synthesize purines de novo; consequently, targeting purine salvage enzymes is a plausible pharmacological strategy. Several enzymes critical to purine metabolism have been studied in T. gondii, but IMP dehydrogenase (IMPDH), which catalyzes the conversion of IMP to XMP, has yet to be characterized. Thus, we have cloned the gene encoding this enzyme in T. gondii. Northern blot analysis shows that two IMPDH transcripts are present in T. gondii tachyzoites. The larger transcript contains an open reading frame of 1,656 nucleotides whose deduced protein sequence consists of 551 amino acids (TgIMPDH). The shorter transcript is an alternative splice product that generates a 371-amino-acid protein lacking the active-site flap (TgIMPDH-S). When TgIMPDH is expressed as a recombinant protein fused to a FLAG tag, the fusion protein localizes to the parasite cytoplasm. Immunoprecipitation with anti-FLAG was employed to purify recombinant TgIMPDH, which converts IMP to XMP as expected. Mycophenolic acid is an uncompetitive inhibitor relative to NAD+, with a intercept inhibition constant (Kii) of 0.03+/-0.004 microM. Tiazofurin and its seleno analog were not inhibitory to the purified enzyme, but adenine dinucleotide analogs such as TAD and the nonhydrolyzable beta-methylene derivatives of TAD or SAD were inhibitory, with Kii values 13- to 60-fold higher than that of mycophenolic acid.

| S-EPMC1140536 | biostudies-literature

Thiophene derivatives activity against the protozoan parasite Leishmania infantum.

Project description:Treatments against leishmaniasis are limited and the development of new molecules is crucial. One class of developmental drug that has shown activity against the parasite Leishmania are thiophene derivatives. Here we synthetized thirty-eight novel thiophene compounds and characterized their activity and potential for resistance against L. infantum. Half of the molecules had an EC50 in the low micromolar range, the piperidine derivatives being more potent than the tetramethylpyran derivatives. Resistance was challenging to select for, and resistant cells could only be raised against one (GC1-19) of the four most active compounds. Using chemogenomic screens we show that a gene conversion event at the ABCG2 locus as well as the overexpression of a tryparedoxin peroxidase are responsible for a weak but significant resistance to the GC1-19 drug candidate. Together, our results suggest that thiophene is a scaffold of interest for further drug development against leishmaniasis.

| S-EPMC9772499 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data