Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Restraint of IFN-γ expression through a distal silencer CNS–28 for tissue homeostasis

ABSTRACT: Interferon-gamma (IFN-gamma) is a key cytokine in response to viral or intracellular bacterial infection in mammals. While a number of enhancers are described to promote IFN-gamma responses, no silencers for the Ifng gene have been identified. By examining H3K4me1 histone modification in naïve CD4+ T cells within Ifng locus, we identified an unrecognized silencer (CNS–28) that is responsible for restraining Ifng expression. Mechanistic study further demonstrates that CNS–28 maintains Ifng silence by diminishing enhancer-promoter interactions within Ifng locus in a T-bet independent manner. Functionally, CNS–28 restrains Ifng transcription in Th1, Tc1, and NK cells during both innate and adaptive immune responses. Moreover, CNS–28 deficiency resulted in repressed type 2 responses due to elevated IFN-gamma expression, shifting Th1 and Th2 paradigm. Thus, CNS–28 activity ensures immune cell quiescence by cooperating with other regulatory cis elements within the Ifng gene locus to minimize autoimmunity.

ORGANISM(S): Mus musculus

PROVIDER: GSE204946 | GEO | 2023/03/01

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

The magnitude of IFN-g responses is fine-tuned by DNA architecture and the non-coding transcript of Ifng-as1

Project description:IFN-g, critical for host defense and tumor surveillance, requires tight control of its expression. Multiple cis-regulatory elements exist around Ifng along with a non-coding transcript, Ifng-as1 (also termed NeST). Here, we describe two genetic models generated to dissect the molecular functions of this locus and its RNA product. DNA Deletion within the Ifng-as1 locus disrupted chromatin organization of the extended Ifng locus, impaired IFN-g response and compromised host defense. Insertion of a polyA signal ablated the Ifng-as1 full-length transcript and impaired host defense, while allowing proper chromatin structure. Transient knockdown of Ifng-as1 also reduced IFN-g production. In humans, discordant expression of IFNG and IFNG-AS1 was evident in memory T cells, with high expression of this lncRNA and low expression of the cytokine. These results establish Ifng-as1 as an important regulator of Ifng expression, as a DNA element and transcribed RNA, involved in dynamic and cell state-specific responses to infection.

2019-07-19 | GSE132531 | GEO

Conserved and cell type-specific transcriptional responses to IFN-γ in the ventral midbrain

Project description:Dysregulated inflammation within the central nervous system (CNS) contributes to neuropathology in infectious, autoimmune, and neurodegenerative disease. With the exception of microglia, major histocompatibility complex (MHC) proteins are virtually undetectable in the mature, healthy central nervous system (CNS). Neurons have generally been considered incapable of antigen presentation, and although interferon gamma (IFN-γ) can elicit neuronal MHC class I (MHC-I) expression and antigen presentation in vitro, it remains unclear whether similar responses occur in vivo. Here we directly injected IFN-γ into the ventral midbrain of mature mice and analyzed gene expression profiles of specific CNS cell types. We find that IFN-γ induces cellular proliferation and expression of MHC-II and associated genes only in microglia. However, IFN-γ upregulated MHC-I and associated mRNAs in ventral midbrain microglia, astrocytes, oligodendrocytes, and GABAergic, glutamatergic, and dopaminergic neurons. The core set of IFN-γ-induced genes and their response kinetics were conserved across neurons and glia, with a lower amplitude of expression in neurons. A diverse repertoire of genes was upregulated in glia, particularly microglia, while no neuron-specific responses to IFN-γ were observed. Using mutant mice to selectively delete the IFN-γ-binding domain of IFNGR1 in dopaminergic neurons, we demonstrate that dopaminergic neurons respond directly to IFN-γ. Our results suggest that most neurons are capable of responding directly to IFN-γ and upregulating MHC-I and related genes in vivo, but their expression amplitude and repertoire is limited compared to oligodendrocytes, astrocytes, and microglia.

2022-12-10 | GSE218132 | GEO

Distinct roles for IL-27 and IFN-g in the development of T-bet+ Treg required to limit infection-induced pathology

Project description:IL-27 is a potent antagonist of TH1-mediated inflammation, but the basis for this effect is not fully understood. Recent studies identified a population of T-bet+ CXCR3+ Treg that limit TH1-mediated immune pathology. The studies presented here demonstrate that IL-27-mediated STAT1 activation promotes Treg expression of T-bet and CXCR3. Infection with Toxoplasma gondii induced a similar Treg population that limits T cell responses and this population at mucosal sites is IL-27-dependent. Furthermore, transfer of Treg ameliorated the infection-induced CD4+ T cell-mediated pathology observed in IL-27p28-/- mice. Although IFN-γ promoted a similar population of cells in the periphery, it did not compensate for the absence of IL-27 at mucosal sites and microarray analysis revealed that Treg exposed to either cytokine have distinct transcriptional profiles. These findings suggest that IFN-γ and IL-27 have different roles in Treg biology but define IL-27 as a key cytokine that promotes the development of Treg specialized to control TH1 immunity. Three conditions were analyzed across two timepoints. Inducible regulatory T cells (iTreg) were generated in vitro in the presence of IL-27, IFNg or under 'Neutral' conditions as a control. Samples were collected at 10 hours and 2 days during the culture period. Three biological replicates were used for each condition.

2012-09-07 | E-GEOD-38686 | biostudies-arrayexpress

EAE_CD3_Sp/Br

Project description:Experimental autoimmune encephalomyelitis (EAE) is the most widely used rodent model for multiple sclerosis. Interferon-γ (IFN-γ) and regulatory T cells (Tregs) are individually well known to play beneficial roles in amelioration of EAE. However, little is known about the relationship between IFN-γ and Tregs during the disease. Here we show that IFN-γ polarizes Tregs into Th1-type Tregs (Th1-Tregs) to recover from EAE. Single-cell RNA sequencing analysis revealed that brain Tregs showed signs of IFN-γ stimulation during EAE. Loss of IFN-γ signaling in Tregs and of T cell-derived IFN-γ impaired the Th1-Treg polarization and worsened the disease. Moreover, selective ablation of Th1-Tregs using an intersectional genetic method promoted pro-inflammatory features of macrophages in the inflamed brains and exacerbated the EAE. Taken together, our study highlights a critical role of T cell-derived IFN-γ for Th1-Treg polarization in inflamed brain to ameliorate EAE.

2024-11-06 | GSE254051 | GEO

EAE_CD4IFNGcKO_CD3

2024-11-06 | GSE254050 | GEO

Global metabolomics of IFNy cued neurogenic NSCs seeded on hydrogel

Project description:Neural stem cells (NSCs) provide a strategy to replace damaged neurons following traumatic central nervous system injuries. A major hurdle to translation of this therapy is that direct application of NSCs to CNS injury does not support sufficient neurogenesis due to lack of proper cues. To provide prolonged spatial cues to NSCs IFN-γ was immobilized to biomimetic hydrogel substrate to supply physical and biochemical signals to instruct the encapsulated NSCs to be neurogenic. However, the immobilization of factors, including IFN-γ, versus soluble delivery of the same factor, has been incompletely characterized especially with respect to activation of signaling and metabolism in cells over longer time points. In this study, protein and metabolite changes in NSCs induced by immobilized versus soluble IFN-γ at 7 days were evaluated. Soluble IFN-γ, refreshed daily over 7 days, elicited stronger responses in NSCs compared to immobilized IFN-γ indicating that immobilization may not sustain signaling or has altered ligand/receptor interaction and integrity. However, both IFN-γ delivery types supported increased βIII tubulin expression in parallel with canonical and non-canonical receptor-signaling compared to no IFN-γ. Global metabolomics and pathway analysis revealed that soluble and immobilized IFN-γ altered metabolic pathway activities including energy, lipid and amino acid synthesis, with soluble IFN-γ having the greatest metabolic impact overall.

2020-09-11 | ST001492 | MetabolomicsWorkbench

Global Mapping of Histone H3 K4 and K27 Trimethylation: Lineage Fate Determination of Differentiating CD4+ T Cells

Project description:Multipotential naïve CD4+ T cells differentiate into distinct lineages including Th1, Th2, Th17, and inducible T regulatory (iTreg) cells. The remarkable diversity of CD4+ T cells begs the question whether the observed changes reflect terminal differentiation with heritable epigenetic modifications or plasticity in T cell responses. We generated genome-wide histone H3 lysine 4 (H3K4) and lysine 27 (H3K27) trimethylation maps in naïve, Th1, Th2, Th17, iTreg, and natural (n)Treg cells. We find that while modifications of signature cytokine genes (Ifng, Il4, and Il17) partially conform to the expectation of lineage commitment, critical transcription factors such as Tbx21 exhibit a broad spectrum of epigenetic states, consistent with our demonstration of T-bet and IFN-γ induction in nTreg cells. Our data suggest an epigenetic mechanism underlying the specificity and plasticity of effector and regulatory T cells and also provide a framework for understanding complexity of CD4+ T helper cell differentiation. genome-wide analysis of histone H3 K4 and K27 trimethylation in different sub-lineages of mouse CD4+ T cells. (12 samples in total)

2009-01-21 | E-GEOD-14254 | biostudies-arrayexpress

Transcription profiling time series of the response of human microglial cells to interferon gamma

Project description:Microglial cells are resident macrophages in the central nervous system (CNS) and play a pivotal role in the innate and adaptive immune responses against microbial infections. The immune functions of microglia are regulated by a milieu of cytokines including interferon (IFN)-gamma. We here performed a series of experiments to acertain the transcriptional profile of human fetal microglial cells at 1, 6, and 24 h after IFN-gamma treatment. Primary human microglial cells were either untreated or treated with 200u/ml IFN-gamma. Affymetrix U133A chips were utilized. Four different tissue samples (B18, O, W, and Y20) were analyzed at the three time points.

2007-08-03 | E-GEOD-1432 | biostudies-arrayexpress

Autoimmune antigen and serum factor antigen reactivity in a cohort of patients with mycobacterium infection shown previously to be positive and negative for IgG autoantibodies to IFN-gamma.

Project description:The aim of the study was to test wether our microarray platform is capable of detecting previously described IgG autoantibodies to IFN-gamma. We diluted patient sera 1:250 and incubated dilutions on a nitrocellulose-platform array printed with whole protein antigens. In this study, serum from 10 individuals (subsetted into two groups: individuals positive or negative for previously described IFN-gamma-targeted autoantibodies) was profiled for IgG autoantibody reactivity to whole protein autoimmune and serum factor antigens. We found that IFN-gamma-targeted IgG autoantibodies were recognized in the IFNg-pos samples and also identified other array targets significantly associated with anti-IFNg positive individials using the significance analysis of microarrays (SAM) algorithm.

2013-09-24 | E-GEOD-51102 | biostudies-arrayexpress

Blimp-1 and c-Maf regulate Il10 and negatively regulate common and unique proinflammatory gene networks in IL-12 plus IL-27-driven T helper-1 cells [ATAC-Seq]

Project description:CD4+ Th1 cells producing IFN-g are required to eradicate intracellular pathogens, however if uncontrolled these cells can mediate immunopathology. The cytokine IL-10 is produced by multiple immune cells including Th1 cells during infection and regulates the immune response to minimise collateral host damage. In this study we aimed to elucidate the transcriptional network of genes controlling the expression of Il10 and proinflammatory cytokines, including Ifng in Th1 cells. We show that the transcription factors Blimp-1 and c-Maf each have unique and common effects on cytokine gene regulation and not only co-operate to induce Il10 gene expression in IL-12 plus IL-27 differentiated Th1 cells, but additionally directly negatively regulate key proinflammatory cytokines including Ifng, thus providing mechanisms for reinforcement of regulated Th1 cell responses.

2023-08-24 | GSE197782 | GEO

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