Identify the key signaling pathway involved in the Tet2 deficiency-induced clonal hematopoiesis
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE232384 | GEO | 2023/05/15
REPOSITORIES: GEO
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Project description:Clonal hematopoiesis of indeterminate potential is prevalent in elderly individuals and associated with increased risks of all-cause mortality and cardiovascular disease. However, mouse models to study the dynamics of clonal hematopoiesis and its consequences on the cardiovascular system under homeostatic conditions are lacking. We used a model of clonal hematopoiesis using adoptive transfer of unfractionated ten-eleven translocation 2-mutant (Tet2-mutant) bone marrow cells into nonirradiated mice. Consistent with age-related clonal hematopoiesis observed in humans, these mice displayed a progressive expansion of Tet2-deficient cells in multiple hematopoietic stem and progenitor cell fractions and blood cell lineages. The expansion of the Tet2-mutant fraction was also observed in bone marrow-derived CCR+ myeloid cell populations within the heart, but there was a negligible impact on the yolk sac-derived CCR2- cardiac resident macrophage population. Transcriptome profiling revealed an enhanced inflammatory signature in the donor-derived macrophages isolated from the heart. Mice receiving Tet2-deficient bone marrow cells spontaneously developed age-related cardiac dysfunction characterized by greater hypertrophy and fibrosis. Altogether, we show that Tet2- mediated hematopoiesis contributes to cardiac dysfunction in a nonconditioned setting that faithfully models the human clonal hematopoiesis in unperturbed bone marrow. Our data support clinical findings that clonal hematopoiesis per se may contribute to diminished health span.
2020-03-12 | GSE146812 | GEO
Project description:Activation of the STING (Stimulator of Interferon Genes) pathway by microbial or self-DNA, as well as cyclic di nucleotides (CDN), results in the induction of numerous genes that suppress pathogen replication and facilitate adaptive immunity. However, sustained gene transcription is rigidly prevented to avoid lethal STING-dependent pro-inflammatory disease by mechanisms that remain unknown. We demonstrate here that after autophagy-dependent STING delivery of TBK1 (TANK-binding kinase 1) to endosomal/lysosomal compartments and activation of transcription factors IRF3 (interferon regulatory factors 3) and NF-κB (nuclear factor kappa beta), that STING is subsequently phosphorylated by serine/threonine UNC-51-like kinase (ULK1/ATG1) and IRF3 function is suppressed. ULK1 activation occurred following disassociation from its repressor adenine monophosphate activated protein kinase (AMPK), and was elicited by CDN’S generated by the cGAMP synthase, cGAS. Thus, while CDN’s may initially facilitate STING function, they subsequently trigger negative-feedback control of STING activity, thus preventing the persistent transcription of innate immune genes. Total RNA obtained from primary STING deficient mouse embryonic fibroblast reconstituted with mSTING (W), S365A variant (A), or S365D variant (D). These cells were transfected with dsDNA (ISD) for 3 hours.
2013-10-10 | E-GEOD-51199 | biostudies-arrayexpress
Project description:Genome-wide association studies (GWAS) have identified over 800 loci associated with kidney function, yet the specific genes, variants, and pathways involved remain elusive. By integrating kidney function GWAS, human kidney expression and methylation quantitative trait analyses, we identified Ten-Eleven Translocation (TET) DNA demethylase 2: TET2 as a novel kidney disease risk gene. Utilizing single-cell chromatin accessibility and CRISPR-based genome editing, we highlight GWAS variants that influence TET2 expression in kidney proximal tubule cells. Experiments using kidney/tubule-specific Tet2 knockout mice indicated its protective role in cisplatin-induced acute kidney injury, as well as chronic kidney disease and fibrosis, induced by unilateral ureteral obstruction or adenine diet. Single-cell gene profiling of kidneys from Tet2 knockout mice and TET2-knock-down tubule cells revealed the altered expression of DNA damage repair and chromosome segregation genes, notably including INO80, another kidney function GWAS target gene itself. Remarkably both TET2-null and INO80-null cells exhibited an increased accumulation of micronuclei after injury, leading to the activation of cytosolic nucleotide sensor cGAS-STING. Genetic deletion of cGAS or STING in kidney tubules or pharmacological inhibition of STING protected TET2 null mice from disease development. In conclusion, our findings highlight TET2 and INO80 as key genes in the pathogenesis of kidney diseases, indicating the importance of DNA damage repair mechanisms.
2024-09-13 | GSE273027 | GEO
Project description:The DNA exonuclease TREX1 degrades endogenous cytosolic DNA. Cytosolic DNA triggers the cGAS/STING pathway which increases type I interferon. To investigate the physiological significance of TREX1 loss on in vivo tumor growth, we implanted control and TREX1-deficient CT26 tumor cells into immunocompetent BALB/c hosts.Tumor cells were collected 7 days after tumors reached around 200mm3.
2024-03-12 | E-MTAB-13816 | biostudies-arrayexpress
Project description:Gout is a common inflammatory arthritis caused by precipitation of monosodium urate (MSU) crystals in individuals with hyperuricemia. Acute flares are accompanied by secretion of pro-inflammatory cytokines, including interleukin-1 beta (IL-1B). Clonal hematopoiesis of indeterminate potential (CHIP) is an age-related condition predisposing to hematologic cancers and cardiovascular disease. CHIP is associated with elevated IL-1B, thus we investigated CHIP as a risk factor for gout. To test the clinical association between CHIP and gout, we analyzed whole exome sequencing data from 177,824 individuals in the MGB Biobank (MGBB) and UK Biobank (UKB). In both cohorts, the frequency of gout was higher among individuals with CHIP than without CHIP (MGBB, CHIP with variant allele fraction [VAF] ≥2%: OR, 1.69; 95% CI, 1.09-2.61; P=0.0189; UKB, CHIP with VAF ≥10%: OR, 1.25; 95% CI, 1.05-1.50; P=0.0133). Moreover, individuals with CHIP and a VAF ≥10% had an increased risk of incident gout (UKB: HR, 1.28; 95% CI, 1.06-1.55; P=0.0107). In murine models of gout pathogenesis, animals with Tet2 knockout hematopoietic cells had exaggerated IL-1B secretion and paw edema upon administration of MSU crystals. Tet2 knockout macrophages elaborated higher levels of IL-1B in response to MSU crystals in vitro, and this was ameliorated through genetic and pharmacologic Nlrp3 inflammasome inhibition. These studies show that TET2-mutant CHIP is associated with an increased risk of gout in humans and that MSU crystals lead to elevated IL-1B levels in Tet2 knockout murine models. We identify CHIP as an amplifier of NLRP3-dependent inflammatory responses to MSU crystals in gout patients.
2022-06-14 | GSE205963 | GEO
Project description:Mounting evidence demonstrates that cGAS-STING signaling is the major pathway in sensing cytosolic DNAs. However, aberrant accumulation of self DNA molecules in Trex1 (a 3'-to-5' DNA exonuclease) deficient cells usually causes over-activation of cGAS-STING signaling, which is associated with the pathology of several autoimmune diseases. Here, we investigated gene expression changes in BMDM cells of Trex1 knockout mice after manipulating cGAS-STING signaling activity via treatment of two STING antagonists (SN-011 and H151) .
2021-05-26 | GSE143830 | GEO
Project description:Clonal hematopoiesis of indeterminate potential (CHIP), also referred to as aging-related clonal hematopoiesis, is defined as an asymptomatic clonal expansion of mutant mature hematopoietic cells in ≥4% of blood leukocytes. CHIP associates with advanced age and increased risk for hematological malignancy, cardiovascular disease, and all-cause mortality. Loss-of-function somatic mutations in TET2 are frequent drivers of CHIP. However, the contribution of aging-associated cooperating cell-extrinsic drivers, like inflammation, remains underexplored. Using bone marrow (BM) transplantation and newly developed genetic mosaicism (HSC-SCL-Cre-ERT; Tet2+/flox; R26+/tm6[CAG-ZsGreen1]Hze) mouse models of Tet2+/-driven CHIP, we observed an association between increased Tet2+/- clonal expansion and higher BM levels of the inflammatory cytokine interleukin-1 (IL-1) upon aging. Administration of IL-1 to mice carrying CHIP led to an IL-1 receptor 1 (IL-1R1)-dependent expansion of Tet2+/- hematopoietic stem and progenitor cells (HSPCs) and mature blood cells. This expansion was caused by increased Tet2+/- HSPC cell cycle progression, increased multilineage differentiation, and higher repopulation capacity compared with their wild-type counterparts. In agreement, IL-1α-treated Tet2+/- hematopoietic stem cells showed increased DNA replication and repair transcriptomic signatures and reduced susceptibility to IL-1α-mediated downregulation of self-renewal genes. More important, genetic deletion of IL-1R1 in Tet2+/- HPSCs or pharmacologic inhibition of IL-1 signaling impaired Tet2+/- clonal expansion, establishing the IL-1 pathway as a relevant and therapeutically targetable driver of Tet2+/- CHIP progression during aging.
| S-EPMC10651783 | biostudies-literature
Project description:In this study, cisplatin activated cGAS-STING signal pathway and deficiency of STING attenuated cisplatin-induced cardiotoxicity in vivo and in vitro. Mechanistically, STING-TNF-α-AP-1 axis contributed to cisplatin-induced cardiotoxicity by triggering cardiomyocyte apoptosis.
2021-08-12 | GSE181749 | GEO
Project description:Epigenetic reinforcement of T cell exhaustion is a major barrier limiting durability of T cell responses during immunotherapy, however the central epigenetic regulators restricting therapy-enabling T cell stemness in settings of prolonged antigen exposure remain to be fully resolved. Here we investigated DNMT3A, TET2, and ASXL1, the three most commonly mutated epigenetic regulators promoting clonal hematopoiesis (CH), to determine if they control the cardinal features of T cell stemness. Using a canonical murine model of exhaustion, we show that CD8 T cells lacking Dnmt3a, Tet2, or Asxl1 are able to preserve an immune checkpoint blockade (ICB) responsive progenitor-exhausted (Tpex) population for over a year during chronic antigen exposure without undergoing malignant transformation. Specific investigation into the lesser-studied regulator, Asxl1, revealed that this unprecedented maintenance of Tpex was achieved through preservation of the cell’s self-renewal capacity with less terminal differentiation. Mechanistic investigation into the role of Asxl1 during CD8 T cell differentiation revealed epigenetic modification of the PR-DUB pathway involving H2AK119-ubiquitination. Extending this Tpex-preserving mechanism to immunotherapy, we report synergy between Asxl1 deficient T cells and anti-PDL1, resulting in heightened tumor control in murine tumor models and a survival advantage to the mutated T cells in treated patients. These data collectively define a core set of epigenetic regulators that control longevity of the stem-like T cell population responsible for clinical success during cancer immunotherapy.
2024-10-10 | GSE274865 | GEO
Project description:Epigenetic reinforcement of T cell exhaustion is a major barrier limiting durability of T cell responses during immunotherapy, however the central epigenetic regulators restricting therapy-enabling T cell stemness in settings of prolonged antigen exposure remain to be fully resolved. Here we investigated DNMT3A, TET2, and ASXL1, the three most commonly mutated epigenetic regulators promoting clonal hematopoiesis (CH), to determine if they control the cardinal features of T cell stemness. Using a canonical murine model of exhaustion, we show that CD8 T cells lacking Dnmt3a, Tet2, or Asxl1 are able to preserve an immune checkpoint blockade (ICB) responsive progenitor-exhausted (Tpex) population for over a year during chronic antigen exposure without undergoing malignant transformation. Specific investigation into the lesser-studied regulator, Asxl1, revealed that this unprecedented maintenance of Tpex was achieved through preservation of the cell’s self-renewal capacity with less terminal differentiation. Mechanistic investigation into the role of Asxl1 during CD8 T cell differentiation revealed epigenetic modification of the PR-DUB pathway involving H2AK119-ubiquitination. Extending this Tpex-preserving mechanism to immunotherapy, we report synergy between Asxl1 deficient T cells and anti-PDL1, resulting in heightened tumor control in murine tumor models and a survival advantage to the mutated T cells in treated patients. These data collectively define a core set of epigenetic regulators that control longevity of the stem-like T cell population responsible for clinical success during cancer immunotherapy.
2024-10-10 | GSE274864 | GEO