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| Status |
Public on Jan 25, 2012 |
| Title |
Impaired Chromatin Remodelling at STAT1-Regulated Promoters Leads to Global Unresponsiveness of Toxoplasma gondii-Infected Macrophages to IFN-Gamma |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by array
|
| Summary |
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.
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| Overall design |
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.
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| Contributor(s) |
Lang C, Hildebrandt A, Brand F, Opitz L, Dihazi H, Lueder CG |
| Citation missing |
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| |
| Submission date |
Apr 08, 2011 |
| Last update date |
Nov 17, 2012 |
| Contact name |
Gabriela Salinas |
| E-mail(s) |
Gabriela.Salinas-Riester@medizin.uni-goettingen.de
|
| Organization name |
Universitaetsmedizin Goettingen
|
| Department |
Department of Pathology
|
| Lab |
NGS Integrative Genomics
|
| Street address |
Kreuzbergring 57
|
| City |
Goettingen |
| State/province |
Lower-Saxony |
| ZIP/Postal code |
37075 |
| Country |
Germany |
| |
|
| Platforms (1) |
| GPL7042 |
Agilent-012694 Whole Mouse Genome G4122A (Probe Name version) |
|
| Samples (10)
|
| GSM706137 |
n.i. Untreated vs. T. gondii Untreated |
| GSM706138 |
T. gondii Untreated vs. n.i. Untreated |
| GSM706139 |
n.i. Untreated vs. n.i. IFN-gamma |
| GSM706140 |
n.i. IFN-gamma vs. n.i. Untreated |
| GSM706141 |
n.i. Untreated vs. T. gondii IFN-gamma |
| GSM706142 |
T. gondii IFN-gamma vs. n.i. Untreated |
| GSM706143 |
T. gondii Untreated vs. T. gondii IFN-gamma |
| GSM706144 |
T. gondii IFN-gamma vs. T. gondii Untreated |
| GSM706145 |
n.i. IFN-gamma vs. T. gondii IFN-gamma |
| GSM706146 |
T. gondii IFN-gamma vs. n.i. IFN-gamma |
|
| Relations |
| BioProject |
PRJNA139297 |
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