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Probing the direct differences in TREX1 gene modification in mice.

ABSTRACT: We constructed Trex1-/-, Trex1D18N, Trex1p212fs mice by CRISPR-Cas9 technology. Four genotypes of MEFS, WT, Trex1-/-, Trex1D18N, Trex1p212fs were obtained by isolating 13.5-day mouse embryos, and then second generation MEFs were collected for RNA-seq analysis to explore the differences between cells.

ORGANISM(S): Mus musculus

PROVIDER: GSE226512 | GEO | 2023/07/12

REPOSITORIES: GEO

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Probing the direct differences in TREX1 gene modification in mice.

Project description:Probing the direct differences in TREX1 gene modification in mice.

| PRJNA940459 | ENA

Loss of Trex1 in dendritic cells is sufficient to trigger systemic autoimmunity

Project description:Biallelic defects of the gene encoding for the intracellular enzyme 3â repair exonuclease (Trex)1 cause Aicardi-GoutiÃ¨res syndrome (AGS), a rare monogenic, lupus-like autoimmune disease, while heterozygous Trex1 loss of function alleles are associated with systemic lupus erythematosus (SLE). Trex1-/- mice develop lethal autoimmune multi-organ inflammation, which results from a chronic type I IFN response triggered by intracellular accumulation of a putative nucleic acid substrate of Trex1. This pathogenic nucleic acid is detected by the broadly, but not ubiquitously, expressed cytosolic DNA sensor cGAS, raising the question whether there are specific cell types that respond to Trex1 deficiency by production of IFN and induce autoimmunity. We generated mice with conditional knock out of the Trex1 gene and demonstrated that loss of Trex1 throughout the hematopoietic system and even selective loss in dendritic cells is sufficient to cause IFN release and autoimmunity. B cells showed no transcriptional response to Trex1 deficiency. Trex1-/- keratinocytes produced IFN but did not induce skin inflammation, whereas loss of Trex1 in cardiomyocytes triggered neither IFN response nor pathology. Trex1-deficient neurons and astrocytes did not release IFN in the CNS. In contrast, mice with selective inactivation of Trex1 in long-living CNS macrophages such as microglia locally produced IFN but did not reproduce the mild encephalitis seen in Trex1-/- mice. Collectively, individual cell types differentially respond to the loss of Trex1 and dendritic cells seem promising candidates for experiments addressing the molecular pathomechanism in Trex1 deficiency. We sorted CD19-positive B cells from spleens of Trex1fl/fl CD19-Cre+ and Trex1fl/fl CD19-Cre- mice and isolated total RNA for library construction to perform mRNA deep sequencing.

2016-08-01 | E-GEOD-77693 | biostudies-arrayexpress

CT26 sorted in vivo tumor cells with Trex1 KO

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2024-03-12 | E-MTAB-13816 | biostudies-arrayexpress

Inherited C-terminal TREX1 variants disrupt homology-directed repair to cause senescence and DNA damage phenotypes in Drosophila, mice, and humans

Project description:Age-related microangiopathy, also known as small vessel disease (SVD), causes damage to the liver, brain, kidney and retina. Based on the DNA damage theory of aging, we reasoned that genomic instability may underlie an SVD caused by dominant C-terminal variants in TREX1, the most abundant 3’-5’ DNA exonuclease in mammals. C-terminal TREX1 variants cause an adult-onset SVD known as retinal vasculopathy with cerebral leukoencephalopathy (RVCL or RVCL-S). In RVCL, an aberrant, C-terminally truncated TREX1 mislocalizes to the nucleus due to deletion of its ER-anchoring domain. Since RVCL pathology mimics that of the radiation injury, we reasoned that nuclear TREX1 promotes DNA damage. Here, we show that RVCL-associated TREX1 variants cause DNA damage in humans, mice, and Drosophila, and that cells expressing RVCL mutant TREX1 are more vulnerable to DNA damage induced by chemotherapy and cytokines that up-regulate TREX1, leading to depletion of TREX1-high cells in RVCL mice. RVCL-associated TREX1 mutants inhibit homology-directed repair (HDR), causing DNA deletions and vulnerablility to PARP inhibitors. In women with RVCL, we observe early-onset breast cancer, similar to patients with BRCA1/2 variants. Our results provide a new mechanistic basis linking aberrant TREX1 activity to the DNA damage theory of aging, premature senescence, and microvascular disease.

2024-05-30 | PXD051905 | Pride

Loss of Trex1 in dendritic cells is sufficient to trigger systemic autoimmunity

Project description:Biallelic defects of the gene encoding for the intracellular enzyme 3’ repair exonuclease (Trex)1 cause Aicardi-Goutières syndrome (AGS), a rare monogenic, lupus-like autoimmune disease, while heterozygous Trex1 loss of function alleles are associated with systemic lupus erythematosus (SLE). Trex1-/- mice develop lethal autoimmune multi-organ inflammation, which results from a chronic type I IFN response triggered by intracellular accumulation of a putative nucleic acid substrate of Trex1. This pathogenic nucleic acid is detected by the broadly, but not ubiquitously, expressed cytosolic DNA sensor cGAS, raising the question whether there are specific cell types that respond to Trex1 deficiency by production of IFN and induce autoimmunity. We generated mice with conditional knock out of the Trex1 gene and demonstrated that loss of Trex1 throughout the hematopoietic system and even selective loss in dendritic cells is sufficient to cause IFN release and autoimmunity. B cells showed no transcriptional response to Trex1 deficiency. Trex1-/- keratinocytes produced IFN but did not induce skin inflammation, whereas loss of Trex1 in cardiomyocytes triggered neither IFN response nor pathology. Trex1-deficient neurons and astrocytes did not release IFN in the CNS. In contrast, mice with selective inactivation of Trex1 in long-living CNS macrophages such as microglia locally produced IFN but did not reproduce the mild encephalitis seen in Trex1-/- mice. Collectively, individual cell types differentially respond to the loss of Trex1 and dendritic cells seem promising candidates for experiments addressing the molecular pathomechanism in Trex1 deficiency.

2016-08-01 | GSE77693 | GEO

Microarray of Trex1 WT and Trex1 KO hearts on RAG2KO background

Project description:Heart ventricle tissue was harvested from Trex1/RAG2 DKO mice and from Trex1WT/RAG2KO littermate controls. RNA was extracted, and an Affymetrix Mouse 430 2.0 gene chip analysis was performed.

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Trex1 knock out in cancer cell lines

Project description:We performed bulk RNA-seq on cell lines with and without knock out of the Trex1 gene.

2024-03-12 | E-MTAB-13815 | biostudies-arrayexpress

Transcription profiling of mouse Trex1 WT and Trex1 KO hearts on RAG2KO background

Project description:Heart ventricle tissue was harvested from Trex1/RAG2 DKO mice and from Trex1WT/RAG2KO littermate controls. RNA was extracted, and an affymetrix Mouse 430 2.0 gene chip analysis was performed. Experiment Overall Design: Three pairs of littermates are included: 779/780, 4184/4185, and 4192/4193.

2008-10-25 | E-GEOD-11698 | biostudies-arrayexpress

The exonuclease TREX1 constitutes an innate immune checkpoint limiting cGAS/STING-mediated anti- tumor immunity

Project description:Given that TREX1-deficient tumor cells showed a growth delay in immunocompetent but not immunodeficient hosts, we characterize the consequences of CT26 tumor-intrinsic TREX1 loss on the host immune system by performing single-cell RNA sequencing on intra-tumoral immune cells sorted from control and TREX1 KO CT26 tumors.

2024-03-12 | E-MTAB-13823 | biostudies-arrayexpress

Single-cell sequencing of CD45-positive and CD45 negative cells from the lungs of WT, Trex1 KO, Trex1;Ifngr1 DKO, and cGas-KI/+;Vav-icre mice

Project description:Trex1 KO is one of the animal models with activated cGAS. Here, we will compare the lung tissue of mice with hematopoietic overexpression of cGAS to see if it exhibits a phenotype similar to that of Trex1 KO.

2024-07-09 | GSE271340 | GEO

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