Dataset Information

MS-based quantitative proteomic analysis of total proteomes from T. gondii strains upon MORC’s depletion and TgHDAC3 inhibition.

ABSTRACT: T. gondii has a complex life cycle typified by an asexual development taking place in vertebrate, and a sexual reproduction which occurs exclusively in felids and thereby is less studied. The developmental transitions rely on changes in gene expression patterns, and recent studies have assigned roles for chromatin shapers, including histone modifications, in establishing specific epigenetic programs for each given stage. Here, we identified T. gondii microrchidia (MORC) protein as an upstream transcriptional repressor of sexual commitment. To explore the molecular role of MORC, we conducted mass spectrometry-based quantitative proteomic analyses to monitor the proteome changes upon MORC’s depletion and TgHDAC3 inhibition.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Toxoplasma Gondii

SUBMITTER: Yohann Couté

LAB HEAD: Virginie Brun

PROVIDER: PXD016845 | Pride | 2020-01-09

REPOSITORIES: Pride

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Publications

A MORC-driven transcriptional switch controls Toxoplasma developmental trajectories and sexual commitment.

Farhat Dayana C DC Swale Christopher C Dard Céline C Cannella Dominique D Ortet Philippe P Barakat Mohamed M Sindikubwabo Fabien F Belmudes Lucid L De Bock Pieter-Jan PJ Couté Yohann Y Bougdour Alexandre A Hakimi Mohamed-Ali MA

Nature microbiology 20200224 4

Toxoplasma gondii has a complex life cycle that is typified by asexual development that takes place in vertebrates, and sexual reproduction, which occurs exclusively in felids and is therefore less studied. The developmental transitions rely on changes in the patterns of gene expression, and recent studies have assigned roles for chromatin shapers, including histone modifications, in establishing specific epigenetic programs for each given stage. Here, we identified the T. gondii microrchidia (M ...[more]

PMID: 32094587

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Project description:Intracellular pathogens including the apicomplexan and opportunistic parasite Toxoplasma gondii profoundly modify their host cells in order to establish infection. We have shown previously that intracellular T. gondii inhibit up-regulation of regulatory and effector functions in murine macrophages (MΦ) stimulated with interferon (IFN)-γ, which is the cytokine crucial for controlling the parasites’ replication. Using genome-wide transcriptome analysis we show herein that infection with T. gondii leads to global unresponsiveness of murine macrophages to IFN-γ. More than 61% and 89% of the transcripts, which were induced or repressed by IFN-γ in non-infected MΦ, respectively, were not altered after stimulation of T. gondii-infected cells with IFN-γ. These genes are involved in a variety of biological processes, which are mostly but not exclusively related to immune responses. Analyses of the underlying mechanisms revealed that IFN-γ-triggered nuclear translocation of STAT1 still occurred in Toxoplasma-infected MΦ. However, STAT1 bound aberrantly to oligonucleotides containing the IFN-γ-responsive gamma-activated site (GAS) consensus sequence. Conversely, IFN-γ did not induce formation of active GAS-STAT1 complexes in nuclear extracts from infected MΦ. Mass spectrometry of protein complexes bound to GAS oligonucleotides showed that T. gondii-infected MΦ are unable to recruit non-muscle actin to IFN-γ-responsive DNA sequences, which appeared to be independent of stimulation with IFN-γ and of STAT1 binding. IFN-γ-induced recruitment of BRG-1 and acetylation of core histones at the IFN-γ-regulated CIITA promoter IV, but not β-actin was diminished by >90% in Toxoplasma-infected MΦ as compared to non-infected control cells. Remarkably, treatment with histone deacetylase inhibitors restored the ability of infected macrophages to express the IFN-γ regulated genes H2-A/E and CIITA. Taken together, these results indicate that Toxoplasma-infected MΦ are unable to respond to IFN-γ due to disturbed chromatin remodelling, but can be rescued using histone deacetylase inhibitors. Comparison of 4 different RNA pools with a 2-Color-Loop Design including 10 microarrays: [1] T. gondii infected and IFN-gamma treated, [2] T. gondii infected and untreated, [3] Non-infected and IFN-gamma treated, and [4] Non-infected and untreated.

Dataset Information

MS-based quantitative proteomic analysis of total proteomes from T. gondii strains upon MORC’s depletion and TgHDAC3 inhibition.

Publications

A MORC-driven transcriptional switch controls Toxoplasma developmental trajectories and sexual commitment.

Similar Datasets

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