The lipid metabolism enzyme DGAT1 mediates regulatory T cell control of type 2 antibody responses
Ontology highlight
ABSTRACT:
INSTRUMENT(S): Illumina HiSeq 4000
ORGANISM(S): Mus musculus
SUBMITTER: Nicholas Ilott
PROVIDER: E-MTAB-12226 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
Similar Datasets
Project description:Regulatory T cells were sorted from the colon of mice under steady state conditions from mice that were either wild type or Dgat1 knockout. To gain enough cells for sequencing samples from the same group were pooled (n=5/pool).
2023-01-01 | E-MTAB-9477 | biostudies-arrayexpress
Project description:Enhanced fatty acid (FA) synthesis and uptake underpin the sustained membrane biogenesis and ATP production required for melanoma cell growth and division1-4. However, to thrive, melanoma cells must avoid a potential reduction in cell growth signalling, rampant reactive oxygen species (ROS) generation, and the build-up of toxic lipid species that can accompany excess free FA5. Here, we uncover and address the significance of frequent amplification and up-regulation of the Diacylglycerol O-acyltransferase 1 (DGAT1) gene in melanoma, whose encoded product catalyses the final step of Triacyglyceride (TAG) synthesis. Consistent with the classification of DGAT1 as an oncogene, we found that forced DGAT1 expression in p53 mutant zebrafish melanocytes was sufficient to induce melanoma, and accelerated melanoma progression initiated by co-expression of oncogenic BRAF or NRAS. Regarding DGAT1 function in human melanoma cells, its depletion, or alternatively pharmacological inhibition, suppressed mTOR-S6K signalling and increased levels of acyl carnitine species— FA derivatives that are the limiting substrate for FA oxidation (FAO). In turn, increased FAO induced mitochondrial malfunction, ROS generation, and lipid peroxidation. However, the resultant oxidative stress induced NRF2 and SESTRIN2 (SESN2) expression, which limited the extent of cell death. Conversely, DGAT1 over-expression enhanced mTOR-S6K signalling and cell growth, and protected against ROS, particularly in hypoxic conditions. Together, our data establish DGAT1 as a bona fide oncogene essential in melanoma cells for enabling FA accumulation.
2023-03-10 | PXD017487 | Pride
Project description:Inhibition of Diacylglycerol O-acyltransferase 1 (DGAT1) has been a mechanism of interest for metabolic disorders. DGAT1 inhibition has been shown to be a key regulator in an array of metabolic pathways; however, based on the DGAT1 KO mouse phenotype the anticipation is that pharmacological inhibition of DGAT1 could potentially lead to skin related adverse effects. One of the aims in developing small molecule DGAT1 inhibitors that target key metabolic tissues is to avoid activity on skin-localized DGAT1 enzyme. In this report we describe a modeling-based approach to identify molecules with physical properties leading to differential exposure distribution. In addition, we demonstrate histological and RNA based biomarker approaches that can detect sebaceous gland atrophy pre-clinically that could be used as potential biomarkers in a clinical setting. Mice were treated with DGAT1 inhibitors for 14 days and dorsal skin biopsies (3-5 mm^2) were taken. RNA was profiled on custom Affymetrix microarrays. The primary goal was to identify robust and consistent biomarkers of DGAT1 inibition in skin.
2014-02-20 | E-GEOD-49375 | biostudies-arrayexpress
Project description:Inhibition of Diacylglycerol O-acyltransferase 1 (DGAT1) has been a mechanism of interest for metabolic disorders. DGAT1 inhibition has been shown to be a key regulator in an array of metabolic pathways; however, based on the DGAT1 KO mouse phenotype the anticipation is that pharmacological inhibition of DGAT1 could potentially lead to skin related adverse effects. One of the aims in developing small molecule DGAT1 inhibitors that target key metabolic tissues is to avoid activity on skin-localized DGAT1 enzyme. In this report we describe a modeling-based approach to identify molecules with physical properties leading to differential exposure distribution. In addition, we demonstrate histological and RNA based biomarker approaches that can detect sebaceous gland atrophy pre-clinically that could be used as potential biomarkers in a clinical setting.
2014-02-20 | GSE49375 | GEO
Project description:Ferroptosis, a form of regulated cell death driven by lipid peroxidation, has emerged as a promising mechanism in cancer therapy. However, the lack of clinically viable ferroptosis inducers has precluded its therapeutic evaluation in patients. Here, we demonstrate that inhibition of diacylglycerol O-acyltransferase 1 (DGAT1) induces a ferroptosis-like phenotype in cancer cells and enhances the efficacy of immune checkpoint blockade (ICB) therapy. In human cancer cohorts, low DGAT1 expression correlated with improved prognosis and elevated ferroptosis-associated gene signatures. In murine models, both genetic knockout and pharmacological inhibition of DGAT1 enhanced ICB therapy efficacy by promoting increased infiltration of cytotoxic T lymphocytes (CTLs). Mechanistically, DGAT1 inhibition reduced lipid droplet (LD) accumulation, triggering elevated lipid peroxidation, mitochondrial dysfunction, and reactive oxygen species (ROS) production. These events culminated in glutathione peroxidase 4 (GPX4) depletion and ferroptosis. Given the availability of clinical-stage DGAT1 inhibitors, our findings provide a strong rationale for repurposing these agents as ferroptosis inducers to enhance cancer immunotherapy.
2026-02-25 | GSE292109 | GEO
Project description:Clear cell renal cell carcinoma (ccRCC) represents a lethal disease and classically resistant to cytotoxic chemotherapy, highlighting the importance of identifying new therapeutic vulnerabilities. We performed a functional siRNA screening for all 2-oxoglutarate (2-OG)-dependent enzymes in ccRCC using 3-D soft agar colony formation assay, and combined with TCGA data, we identified Jumonji domain-containing 6 (JMJD6) as an essential gene for ccRCC tumorigenesis. Downregulation of JMJD6 abolished ccRCC colony formation in vitro and inhibited orthotopic tumor growth in vivo. Integrated analyses of ChIP-seq and RNA-seq identified that JMJD6 can transcriptionally regulate the expression of diacylglycerol O-acyltransferase 1 (DGAT1) by co-occupying the target gene promoter with H3K4me3. Downregulation of JMJD6 caused decreased expression of DGAT1 at both mRNA and protein level. Inhibition or depletion of DGAT1 induced decreased cell growth in vitro or inhibited tumor growth in vivo. Mechanistically, decreased DGAT1 caused decreased LD formation in ccRCC, while restoration of JMJD6 expression can restore DGAT1 level, and LD formation as well as cell growth. In summary, JMJD6 is essential for ccRCC lipid storage and tumorigenesis through a DGAT1-dependent signaling. Therefore, the JMJD6-DGAT1 axis serves as a potential therapeutic avenue for ccRCC.
2022-06-27 | GSE182888 | GEO
Project description:Global transcript profiling of Arabidopsis dgat1-1 seed at different stages of embryo development was used to identify differentially expressed genes in the mutant compared to wild-type (Col-0) seed. These genes provided information about the remodeling of lipid metabolism and TAG synthesis in response to the lack of DGAT1 activity.
2019-08-20 | GSE123303 | GEO
Project description:The role of fatty acid (FA) oxidation 31 in T cell responses has been extensively studied, but whether FA esterification to triacylglycerol (TAG) regulates T cell exhaustion is unknown. Dgat1 catalyzes the rate-limiting step in TAGsynthesis. Here,we showthat deficiency in Dgat1 improvedmitochondrial metabolic fitness and expanded the pool of progenitors of CD8+ exhausted T (Tex) cells to sustain antitumor responses in femalemice. Inmalemice, however, Dgat1 deficiency synergized with androgen receptor (AR) signaling to cause FA peroxidation, endoplasmic reticulum (ER) stress, and Tex cell death. Deletion of Ar, overexpression of glutathione peroxidase 4 (Gpx4), or inhibition of ER stress-induced cell death rescued Dgat1-deficient CD8+ T cell survival and promoted antitumor responses in male mice. This study suggests that Dgat1 detoxifies AR signaling to protect against ER stress-induced cell death and maintain T cell stemness in males, and highlights sex-specific metabolic adaptations in the tumormicroenvironment.
2025-12-16 | GSE307220 | GEO
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
Project description:Thlaspi arvense (field pennycress) is an emerging oilseed crop closely related to Arabidopsis thaliana. Prior research on oilseed species has demonstrated that seed specific upregulation of WRINKLED1 (WRI1), a key regulator of triacylglycerol (TAG) biosynthesis, can augment seed oil content. This phenomenon extends to the TAG biosynthetic enzyme diglyceride acyltransferase 1 (DGAT1). In this study, we show that stable co-expression of WRI1 and DGAT1 in pennycress during seed development significantly elevates oil content in mature seeds. Utilizing in vitro cultured developing embryos, we thoroughly characterized the alterations in seed composition resulting from WRI1/DGAT1 overexpression, employing a combination of transcriptomic analysis, targeted metabolomics, and metabolic flux analysis.
2026-03-19 | GSE283815 | GEO