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Prmt5 deficiency inhibits CD4+T cells migration through Klf2-S1pr1 and ameliorates EAE disease (RNA-seq)

ABSTRACT: Protein arginine methyltransferase 5 (Prmt5) is the major type II methyltransferase catalyzing symmetric dimethylation, regulates cell development, homeostatic and disease processes. Prmt5 inhibition or deletion in CD4+T cells has been reported to protection against experimental autoimmune encephalomyelitis (EAE), the perfect mouse model for multiple sclerosis (MS); however, the detail mechanisms have not yet been elucidated. Here, using the mRNA sequencing, single cell RNA sequencing and ATAC sequencing, we uncovered the unreported role of Prmt5 on T cells migration ability under the EAE condition. We found that mice condition knockout of Prmt5 in T cells were resistance with EAE, infiltrating inflammatory CD4+ T cells in center nervous system (CNS) were greatly reduced. However, T cells in spleen showed much more proliferation and activation properties in Prmt5cko mice, the number of pathogenic CD4+T cells in spleen were not reduced. We further revealed that Rora+CD4+T cells were elevated in Prmt5cko mice, but expressed lower level of S1pr1, resulting in a lack of CD4+ T cells egress from spleen and migrate to CNS, leading to pathogenic CD4+T cells were blocked in spleen. Moreover, single cell ATAC sequencing revealed that Klf2 were enriched in S1pr1 promoter and reduced in Prmt5cko mice. Correctively, our study delineated the undiscovered role of Prmt5 on T cell biology, Prmt5 may through Klf2-S1pr1 pathway and regulate T cells migration; modulating Prmt5 levels may be useful for controlling CD4+T cell migration in CD4+T cell mediated diseases including MS.

ORGANISM(S): Mus musculus

PROVIDER: GSE195874 | GEO | 2023/08/09

REPOSITORIES: GEO

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Prmt5 deficiency inhibits CD4+T cells migration through Klf2-S1pr1 and ameliorates EAE disease (scRNA-seq)

Project description:Protein arginine methyltransferase 5 (Prmt5) is the major type II methyltransferase catalyzing symmetric dimethylation, regulates cell development, homeostatic and disease processes. Prmt5 inhibition or deletion in CD4+T cells has been reported to protection against experimental autoimmune encephalomyelitis (EAE), the perfect mouse model for multiple sclerosis (MS); however, the detail mechanisms have not yet been elucidated. Here, using the mRNA sequencing, single cell RNA sequencing and ATAC sequencing, we uncovered the unreported role of Prmt5 on T cells migration ability under the EAE condition. We found that mice condition knockout of Prmt5 in T cells were resistance with EAE, infiltrating inflammatory CD4+ T cells in center nervous system (CNS) were greatly reduced. However, T cells in spleen showed much more proliferation and activation properties in Prmt5cko mice, the number of pathogenic CD4+T cells in spleen were not reduced. We further revealed that Rora+CD4+T cells were elevated in Prmt5cko mice, but expressed lower level of S1pr1, resulting in a lack of CD4+ T cells egress from spleen and migrate to CNS, leading to pathogenic CD4+T cells were blocked in spleen. Moreover, single cell ATAC sequencing revealed that Klf2 were enriched in S1pr1 promoter and reduced in Prmt5cko mice. Correctively, our study delineated the undiscovered role of Prmt5 on T cell biology, Prmt5 may through Klf2-S1pr1 pathway and regulate T cells migration; modulating Prmt5 levels may be useful for controlling CD4+T cell migration in CD4+T cell mediated diseases including MS.

2023-08-09 | GSE195887 | GEO

Prmt5 deficiency inhibits CD4+T cells migration through Klf2-S1pr1 and ameliorates EAE disease (scATAC-seq)

2023-08-09 | GSE195882 | GEO

Protein arginine methyltransferase 5 promotes cholesterol biosynthesis mediated Th17 responses and autoimmunity [Th17]

Project description:Protein Arginine Methyltransferase (PRMT) 5 catalyzes symmetric dimethylation of arginine, a post-translational modification involved in cancer and embryonic development. However, the role and mechanisms by which PRMT5 modulates T helper (Th) cell polarization and autoimmune disease have not yet been elucidated. Here we find that PRMT5 promotes expression of cholesterol biosynthetic pathway enzymes that produce ROR agonists and activate ROR-t, driving Th17 differentiation. Specific loss of PRMT5 in the CD4 Th cell compartment completely protected mice from EAE. We also find that PRMT5 controls thymic and peripheral homeostasis in the CD4 Th cell life cycle, as well as iNK T and CD8 T cell development or maintenance, respectively. This work conclusively demonstrates that PRMT5 expression in recently activated T cells is necessary for expression of a cholesterol biosynthesis metabolic gene expression program that generates ROR-t agonistic activity and promotes Th17 differentiation and EAE. These results point to Th PRMT5 and its downstream cholesterol biosynthesis pathway as promising therapeutic targets in Th17-mediated diseases.

2020-02-27 | GSE141194 | GEO

Protein arginine methyltransferase 5 promotes cholesterol biosynthesis mediated Th17 responses and autoimmunity [CD4 T-cells]

2020-02-27 | GSE141168 | GEO

Quantitative proteome profiling of CNS-infiltrating autoreactive CD4+ cells reveals selective changes during experimental autoimmune encephalomyelitis

Project description:Experimental autoimmune encephalomyelitis (EAE) is a murine model of multiple sclerosis, a chronic neurodegenerative and inflammatory autoimmune condition of the central nervous system (CNS). Pathology is driven by the infiltration of autoreactive CD4+ lymphocytes into the CNS where they attack neuronal sheaths causing ascending paralysis. We used an isotope-coded protein labelling approach to investigate the proteome of CD4+ cells isolated from the spinal cord and brain of mice at various stages of EAE progression in two EAE disease models; PLP139-151-induced relapsing-remitting EAE and MOG35-55-induced chronic EAE, which emulate the two forms of human multiple sclerosis. A total of 1120 proteins were quantified across disease onset, peak-disease and remission phases of disease and of these, 13 up-regulated proteins of interest were identified with functions relating to the regulation of inflammation, leukocyte adhesion and migration, tissue repair and the regulation of transcription/translation. Proteins implicated in processes such as inflammation (S100A4 and S100A9) and tissue repair (Annexin A1), which represent key events during EAE progression were validated by quantitative PCR. This is the first targeted analysis of autoreactive cells purified from the CNS during EAE, highlighting fundamental CD4+ cell-driven processes that occur during the initiation of relapse and remission stages of disease.

2016-07-08 | PXD001011 | Pride

Hobit and Blimp1 instruct a universal transcriptional program of tissue-residency in lymphocytes

Project description:Tissue-resident memory T cells (Trm) permanently localize to portals of pathogen entry, where they provide immediate protection against re-infection. To enforce tissue retention, Trm upregulate CD69 and downregulate molecules associated with tissue egress including CCR7 and S1PR1. Although suppression of the transcription factor KLF2 in Trm prevents S1PR1-driven migration, a Trm-specific transcriptional regulator has not been identified. Here, we show that the transcription factor Hobit is specifically upregulated in Trm and together with related Blimp1, mediates the development of Trm in skin, gut, liver and kidney. Importantly, the Hobit/Blimp1 transcriptional module is also required for other populations of tissue-resident lymphocytes including NKT cells and liver-resident NK cells, all of which share a common transcriptional program that includes repression of Ccr7, S1pr1, and Klf2. Our results identify Hobit and Blimp1 as central regulators of this universal program that instructs tissue retention in diverse tissue-resident lymphocyte populations.

2016-04-25 | GSE79339 | GEO

DGAT1 regulates retinol-dependent regulatory T cell generation and mediates autoimmune encephalomyelitis

Project description:This file contains gene microarray data from FACS purified mouse memory phenotype CD4+ T cells (CD44hiCD45RBloCD25-), which were isolated from lymph node and spinal cord tissues of mice with experimental autoimmune encephalomyelitis (EAE), a widely studied model of human multiple sclerosis (MS). Memory phenotype CD4+ T cells infiltrating the CNS during EAE expressed high levels of mRNA for Dgat1 encoding diacylglycerol-O-acyltransferase-1 (DGAT1). We studied the biology of DGAT1 in EAE models and in assays of T cell differentiation and function.

2016-05-03 | GSE80978 | GEO

Kruppel-like factor 2+ CD4 T cells avert microbiota induced intestinal inflammation [RNA-seq]

Project description:Commensal immune tolerance requires cells that actively sense and suppress inflammation. Here we show this is in large part mediated by CD4 cells that express the transcriptional regulator KLF2. Suppression by KLF2+ CD4 cells requires cell-intrinsic TCR stimulation. To investigate how KLF2 CD4 cells perform this role, gene expression by purified KLF2+ compared with KLF2-negative CD4 cells were evaluated with TCR stimulation in vitro and control non-stimulated cells.

2023-10-22 | GSE236148 | GEO

PRMT5 promotes symmetric dimethylation of RNA processing proteins and modulates activated T cell alternative splicing and Ca2+/NFAT signaling

Project description:Protein Arginine Methyltransferase (PRMT) 5 is the major type 2 methyltransferase catalyzing symmetric dimethylation (SDM) of arginine. PRMT5 inhibition or deletion in CD4 Th cells reduces TcR engagement-induced IL-2 production and Th cell expansion and confers protection against experimental autoimmune encephalomyelitis (EAE), the animal model of Multiple Sclerosis. However, the mechanisms by which PRMT5 modulates T helper (Th) cell proliferation are still not completely understood and neither are the methylation targets in T cells. In this manuscript, we uncover the role of PRMT5 on alternative splicing (AS) in activated T cells and identify several targets of PRMT5 SDM involved in splicing. In addition, we find a possible link between PRMT5 mediated AS of Trpm4 (Transient Receptor Potential Cation Channel Subfamily M Member 4) and TcR/NFAT signaling/IL-2 production. This understanding may guide development of drugs targeting these processes to benefit patients with T cell-mediated diseases.

2021-10-01 | GSE181931 | GEO

RNA seq on SP specific CD8+ T cells, Ly49+ and Ly49-CD8+ T cells from MOG and MOG + SP immunized mice [RNA-Seq]

Project description:In experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis (MS), induction generates successive waves of clonally expanded CD4+, CD8+, and gd+ T cells in the blood and central nervous system, similar to gluten challenge studies of Celiac patients. In MS patients, we also observe major expansions of CD8+ T cells. In EAE, we find that most expanded CD4+ T cells are specific for the inducing myelin peptide MOG35-55 but in contrast, peptide ligands derived from a yeast peptide-MHC display library for some of the clonally expanded CD8+ T cells inhibit disease by suppressing the proliferation of MOG-specific CD4+ T cells. These results suggest the induction of autoreactive CD4+ T cells triggers an opposing mobilization of regulatory CD8+ T cells.

2019-08-08 | GSE130975 | GEO

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