Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA388099 | ENA |
REPOSITORIES: ENA
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Project description:An NF-κB-dependent, lineage-specific transcriptional program regulates Treg identity and function
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Project description:An NF-κB-dependent, lineage-specific transcriptional program regulates Treg identity and function [RNA-seq]
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Project description:N6-methyladenosine (m6A) in messenger RNA (mRNA) regulates immune cells in homeostasis and in response to infection and inflammation. The function of YTHDF2 in the tumor microenvironment (TME) in these contexts has not been explored. We discovered that loss of Ythdf2 in regulatory T (Treg) cells can reduce tumor growth in mice while maintaining peripheral homeostasis. In the tumor microenvironment, Ythdf2-deficient Treg cells have impaired function and poor survival. The elevated tumor necrosis factor (TNF) signaling in the TME grants the location-specific function of YTHDF2, which participates in the feedback regulation of NF-kB signaling by accelerating the degradation of m6A-modified, NF-kB negative regulators, Nlrc3, Nfkbie, and Traf3. TME-specific regulation of Treg by YTHDF2 points to YTHDF2 as a target for anti-cancer immunotherapy, where intratumoral Treg cells can be targeted to enhance antitumor immune response, while avoiding Treg cells in the periphery to minimize undesired inflammations.
2023-06-07 | GSE216959 | GEO
Project description:N6-methyladenosine (m6A) in messenger RNA (mRNA) regulates immune cells in homeostasis and in response to infection and inflammation. The function of YTHDF2 in the tumor microenvironment (TME) in these contexts has not been explored. We discovered that loss of Ythdf2 in regulatory T (Treg) cells can reduce tumor growth in mice while maintaining peripheral homeostasis. In the tumor microenvironment, Ythdf2-deficient Treg cells have impaired function and poor survival. The elevated tumor necrosis factor (TNF) signaling in the TME grants the location-specific function of YTHDF2, which participates in the feedback regulation of NF-kB signaling by accelerating the degradation of m6A-modified, NF-kB negative regulators, Nlrc3, Nfkbie, and Traf3. TME-specific regulation of Treg by YTHDF2 points to YTHDF2 as a target for anti-cancer immunotherapy, where intratumoral Treg cells can be targeted to enhance antitumor immune response, while avoiding Treg cells in the periphery to minimize undesired inflammations.
2023-06-07 | GSE216958 | GEO
Project description:N6-methyladenosine (m6A) in messenger RNA (mRNA) regulates immune cells in homeostasis and in response to infection and inflammation. The function of YTHDF2 in the tumor microenvironment (TME) in these contexts has not been explored. We discovered that loss of Ythdf2 in regulatory T (Treg) cells can reduce tumor growth in mice while maintaining peripheral homeostasis. In the tumor microenvironment, Ythdf2-deficient Treg cells have impaired function and poor survival. The elevated tumor necrosis factor (TNF) signaling in the TME grants the location-specific function of YTHDF2, which participates in the feedback regulation of NF-kB signaling by accelerating the degradation of m6A-modified, NF-kB negative regulators, Nlrc3, Nfkbie, and Traf3. TME-specific regulation of Treg by YTHDF2 points to YTHDF2 as a target for anti-cancer immunotherapy, where intratumoral Treg cells can be targeted to enhance antitumor immune response, while avoiding Treg cells in the periphery to minimize undesired inflammations.
2023-06-07 | GSE230418 | GEO
Project description:Regulatory T (Treg) cells require Foxp3 expression and induction of a specific DNA hypomethylation signature during development, after which Treg cells persist as a self-renewing population that regulates immune system activation. Whether maintenance DNA methylation is required for Treg cell lineage development and stability and how methylation patterns are maintained during lineage self-renewal remain unclear. Here, we demonstrate that the epigenetic regulator Uhrf1 is essential for maintenance of methyl-DNA marks that stabilize Treg cellular identity by repressing effector T cell transcriptional programs. Constitutive and induced deficiency of Uhrf1 within Foxp3+ cells resulted in global yet non-uniform loss of DNA methylation, derepression of inflammatory transcriptional programs, destabilization of the Treg cell lineage, and spontaneous inflammation. These findings support a paradigm in which maintenance DNA methylation is required in distinct regions of the Treg cell genome for both lineage establishment and stability of identity and suppressive function.
2020-08-27 | GSE143973 | GEO
Project description:Regulatory T (Treg) cells require Foxp3 expression and induction of a specific DNA hypomethylation signature during development, after which Treg cells persist as a self-renewing population that regulates immune system activation. Whether maintenance DNA methylation is required for Treg cell lineage development and stability and how methylation patterns are maintained during lineage self-renewal remain unclear. Here, we demonstrate that the epigenetic regulator Uhrf1 is essential for maintenance of methyl-DNA marks that stabilize Treg cellular identity by repressing effector T cell transcriptional programs. Constitutive and induced deficiency of Uhrf1 within Foxp3+ cells resulted in global yet non-uniform loss of DNA methylation, derepression of inflammatory transcriptional programs, destabilization of the Treg cell lineage, and spontaneous inflammation. These findings support a paradigm in which maintenance DNA methylation is required in distinct regions of the Treg cell genome for both lineage establishment and stability of identity and suppressive function.
2020-08-27 | GSE143972 | GEO
Project description:Thymic medullary epithelial cell (mTEC) expression of the autoimmune regulator AIRE, and of tissue-specific antigens, is controlled by members of the non-canonical NF-kB signalling pathway, including RelB and NF-kB2. Of the genes in this pathway, RelB-/- mice develop a particularly severe multi-organ autoimmune syndrome, resembling Foxp3-deficiency. RelB-/- mice have medullary atrophy and few mTECs but the mechanism is unknown. We show that RelB is required for expression of medullary chemokines and mTEC AIRE, selection of a diverse peripheral T cell repertoire, and for peripheral Foxp3+ Treg function. Vβ families of T cells infiltrating diseased peripheral organs and thymic Treg were similarly skewed. Surprisingly, medullary atrophy results from intra-thymic granulocyte infiltration, consequent upon the Th2-mediated autoimmune disease. Dominant tolerance corrects thymic inflammatory disease and loss of thymic function. We demonstrate a reversible RelB-dependent inflammatory mechanism for loss of central tolerance associated with medullary atrophy. Thymi from 4 RelB+/- mice and 3 RelB-/- mice were profiled by microarays
2012-12-27 | E-GEOD-43154 | biostudies-arrayexpress
Project description:The ability of dendritic cells (DC) to initiate immunity and induce antigen-specific tolerance makes DC ideal targets for pharmacological intervention into immune responses. NF-kB factors are a family of transcriptional regulators important for DC development and function. However, the identity of NF-kB target genes that are central to DC biology is largely unknown. In the present study IkBa super repressor (IkBa-SR) and DNA microarray analysis were used to determine the repertoire of NF-kB responsive genes in DC. In DC these genes regulate vital DC functions of antigen uptake and presentation, motility, survival, etc. Taking in account limitations of the genome-wide microarray analysis, generated transcription factor data were confirmed by the independent means of RT-PCR and chromatin immunoprecipitation. Kinetics of NF-kB induction by well-known DC activatory agents TNFa and LPS were further analysed. NF-kB regulated genes can be potentially useful targets for the development of more specific anti-inflammatory agents for clinical applications. Keywords: drug treatment, adenovirus transduction
2012-12-31 | GSE8009 | GEO
Project description:Stringent regulation of TNF signaling prevents aberrant inflammation. TNF engages the canonical NF-kB pathway for activating the RelA:p50 heterodimer, which mediates specific expressions of pro-inflammatory and immune response genes. Importantly, the NF-kB system discriminates between time-varied TNF inputs. Negative feedback regulators of the canonical pathway, including IkBa, thought to ensure transient RelA:p50 responses to brief TNF stimulations. The noncanonical NF-kB pathway controls a separate RelB activity associated with immune differentiation. In a systems modeling approach, we uncovered an unexpected role of p100, a constituent of the noncanonical pathway, in TNF signaling. Brief TNF stimulation of p100-deficient cells produced an additional late NF-kB activity composed of the RelB:p50 heterodimer, which distorted the TNF-induced gene-expression program. Periodic TNF pulses augmented this RelB:p50 activity, which was reinforced by NF-kB-dependent RelB synthesis. In sum, the NF-kB system seems to engage distantly related molecular species for enforcing dynamical and gene controls of immune-activating TNF signaling.
2020-08-22 | GSE119961 | GEO