Mus musculus strain:mouse
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA382873 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR5452380.fastq.gz | Fastqsanger.gz | |||
| SRR5452390.fastq.gz | Fastqsanger.gz | |||
| SRR5452381.fastq.gz | Fastqsanger.gz | |||
| SRR5452391.fastq.gz | Fastqsanger.gz | |||
| SRR5452382.fastq.gz | Fastqsanger.gz |
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Project description:RORgt is known to instruct the differentiation of Th17 cells that mediate the pathogenesis of autoimmune diseases. However, it remains unknown whether RORgt plays a distinct role in the differentiation and effector function of Th17 cells. Here we show that mutation of RORgt lysine 256, a ubiquitination site, to arginine (K256R) separates the RORgt role in these two functions. Preventing ubiquitination at K256 via arginine substitution does not affect RORgt-dependent thymocyte development and Th17 differentiation in vitro and in vivo, however, greatly impaired the pathogenesis of Th17 cell-mediated experimental autoimmune encephalomyelitis (EAE). Mechanistically, K256R mutation impairs RORgt to bind to and activate Runx1 expression critical for Th17-mediated EAE. Thus, RORgt regulates the effector function of Th17 cells in addition to Th17 differentiation. This work informs the development of RORgt-based therapies that specifically target the effector function of Th17 cells responsible for autoimmunity.
2022-10-26 | GSE211414 | GEO
Project description:RORgt is known to instruct the differentiation of Th17 cells that mediate the pathogenesis of autoimmune diseases. However, it remains unknown whether RORgt plays a distinct role in the differentiation and effector function of Th17 cells. Here we show that mutation of RORgt lysine 256, a ubiquitination site, to arginine (K256R) separates the RORgt role in these two functions. Preventing ubiquitination at K256 via arginine substitution does not affect RORgt-dependent thymocyte development and Th17 differentiation in vitro and in vivo, however, greatly impaired the pathogenesis of Th17 cell-mediated experimental autoimmune encephalomyelitis (EAE). Mechanistically, K256R mutation impairs RORgt to bind to and activate Runx1 expression critical for Th17-mediated EAE. Thus, RORgt regulates the effector function of Th17 cells in addition to Th17 differentiation. This work informs the development of RORgt-based therapies that specifically target the effector function of Th17 cells responsible for autoimmunity.
2022-10-26 | GSE211509 | GEO
Project description:In this study, we show that in addition to regulating DP thymocytes survival, RORgT also controls genes that regulate thymocyte migration, proliferation, and T cell receptor (TCR) selection. Strikingly, pharmacological inhibition of RORg skews TCR gene rearrangement, limits T cell repertoire diversity, and inhibits development of autoimmune encephalomyelitis. Thus, targeting RORgT not only inhibits Th17 cell development and function but also fundamentally alters thymic-emigrant recognition of self and foreign antigens.
2016-10-20 | GSE88916 | GEO
Project description:The nuclear receptor REV-ERBa modulates Th17 cell differentiation and function by competing with RORgt
| PRJNA293559 | ENA
Project description:Th17 cells are a helper cell subset of pro-inflammatory T cells, which have diverse functions ranging from neutrophilic-inflammatory responses against pathogens to driving a number of autoimmune diseases. Accumulating evidence indicates that specific cellular lipid metabolic pathways that include fatty acid or cholesterol play an essential role in regulating the differentiation and function of Th17 cells. However, what molecular mechanisms link lipid metabolism and RORgt function during Th17-cell differentiation? By using a combination of a CRISPR- based screening system and a global lipidome analysis, we addressed this question in an effort to identify a specific lipid metabolite that is essential for RORgt-mediated Th17-cell differentiation. We found five lipid enzymes that elicit RORgt activity and constitute a core molecular signature of Th17 cells. Furthermore, although Th17 cells treated with TOFA, which is a ACC1 inhibitor, showed decreased mRNA expression of Th17 specific gene and chromatin accessibility at Th17 cell specific gene loci, we also found that extrinsic supplementation of LPE (1-18:1) restored the phenotype of ACC1-inhibited Th17 cells. Taken together, these series of results indicated that LPE (1-18:1) synthesized from the five lipid metabolic enzymes was required for RORgt to function appropriately in Th17-cell differentiation.
2023-05-08 | GSE230624 | GEO
Project description:Full development of IL-17 producing CD4+ T helper cells (TH17 cells) requires the transcriptional activity of both orphan nuclear receptors RORa and RORgt. Despite this evidence, RORa is considered functionally redundant to RORgt; thus, the function and therapeutic value of RORa in TH17 cells remains underexplored. Using mouse models of autoimmune and chronic inflammation, we show that expression of RORa is required for TH17 cell pathogenicity. T-cell specific deletion of RORa reduced the development of experimental autoimmune encephalomyelitis (EAE) and colitis. Reduced inflammation was associated with decreased TH17 cell development, lower expression of tissue-homing chemokine receptors and integrins, and increased frequencies of Foxp3+ T regulatory (Treg) cells. Importantly, inhibition of RORa with a selective small molecule antagonist largely phenocopied our genetic data, potently suppressing the in vivo development of both chronic/progressive and relapsing/remitting EAE but had no effect on overall thymic cellularity. Furthermore, use of the RORa antagonist effectively inhibited human TH17 cell differentiation and memory cytokine secretion. Together, these data suggest that RORa acts independently of RORgt in programming TH17 pathogenicity and identifies RORa as a safer and more selective therapeutic target for the treatment of TH17-mediated autoimmunity.
2020-10-29 | GSE160327 | GEO
Project description:Two house mouse subspecies occur in Europe, eastern and northern Mus musculus musculus (Mmm) and western and southern Mus musculus domesticus (Mmd). A secondary hybrid zone occurs where their ranges meet, running from Scandinavia to the Black Sea. In this paper, we tested a hypothesis that the apicomplexan protozoan species Cryptosporidium tyzzeri has coevolved with the house mouse. More specifically, we assessed to what extent the evolution of this parasite mirrors divergence of the two subspecies. In order to test this hypothesis, we analysed sequence variation at five genes (ssrRNA, Cryptosporidium oocyst wall protein (COWP), thrombospondin-related adhesive protein of Cryptosporidium 1 (TRAP-C1), actin and gp60) in C. tyzzeri isolates from Mmd and Mmm sampled along a transect across the hybrid zone from the Czech Republic to Germany. Mmd samples were supplemented with mice from New Zealand. We found two distinct isolates of C. tyzzeri, each occurring exclusively in one of the mouse subspecies (C. tyzzeri-Mmm and C. tyzzeri-Mmd). In addition to genetic differentiation, oocysts of the C. tyzzeri-Mmd subtype (mean: 4.24×3.69?m) were significantly smaller than oocysts of C. tyzzeri-Mmm (mean: 4.49×3.90 ?m). Mmm and Mmd were susceptible to experimental infection with both C. tyzzeri subtypes; however, the subtypes were not infective for the rodent species Meriones unguiculatus, Mastomys coucha, Apodemus flavicollis or Cavia porcellus. Overall, our results support the hypothesis that C. tyzzeri is coevolving with Mmm and Mmd.
| S-EPMC4437667 | biostudies-literature
Project description:Consomic (chromosome substitution) strains (CSs) represent the most recent addition to the mouse genetic resources aimed to genetically analyze complex trait loci (QTLs). In this study, we report the development of a set of 28 mouse intersubspecific CSs. In each CS, we replaced a single chromosome of the C57BL/6J (B6) inbred strain (mostly Mus m. domesticus) with its homolog from the PWD/Ph inbred strain of the Mus m. musculus subspecies. These two progenitor subspecies diverged less than 1 million years ago and accumulated a large number of genetic differences that constitute a rich resource of genetic variation for QTL analyses. Altogether, the 18 consomic, nine subconsomic, and one conplastic strain covered all 19 autosomes, X and Y sex chromosomes, and mitochondrial DNA. Most CSs had significantly lower reproductive fitness compared with the progenitor strains. CSs homosomic for chromosomes 10 and 11, and the C57BL/6J-Chr X males, failed to reproduce and were substituted by less affected subconsomics carrying either a proximal, central, or distal part of the respective chromosome. A genome-wide scan of 965 DNA markers revealed 99.87% purity of the B6 genetic background. Thirty-three nonsynonymous substitutions were uncovered in the protein-coding regions of the mitochondrial DNA of the B6.PWD-mt conplastic strain. A pilot-phenotyping experiment project revealed a high number of variations among B6.PWD consomics.
| S-EPMC2259115 | biostudies-literature