Effect of Tet2 deletion on gene expression in liver macrophages in a mouse model of steatohepatitis [sorted]
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE223694 | GEO | 2023/02/07
REPOSITORIES: GEO
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Project description:To investigate the role of hematopoietic Tet2 loss on the development of steatohepatitis, mice were transplanted with wild type or Tet2 deficient bone marrow cells and fed a choline-deficient, L-amino acid-defined, high-fat diet. Gene expression profiling analysis of bulk liver RNA was then performed.
2023-02-07 | GSE223692 | GEO
Project description:To investigate the role of hepatic CYP2B in diet-induced nonalcoholic steatohepatitis (NASH), a Cyp2b triple knockout mouse lacking Cyp2b9, Cyp2b10, and Cyp2b13 was developed using CRISPER/Cas9. Wildtype (WT) and Cyp2b-null mice were fed a normal diet (ND) or a choline-deficient, L-amino acid-defined high-fat diet (CDAHFD), containing 0.1% methionine and 62% fat for 8 weeks. RNA was extracted from the livers of female and male mice from all treatment groups and used for RNA seqencing. RNAseq data demonstrated that a lack of Cyp2b was protective in female but more harmful in male mice. Hepatic gene expression revealed a higher number of phase I-III xenobiotic metabolism and inflammatory response genes were down-regulated in CDAHFD-fed WT female and Cyp2b-null male mice.
2019-12-31 | GSE137449 | GEO
Project description:Transcriptomic profiles of wild type and TSP1 knockout mice that were fed control (normal) diet or CDAHFD (choline deficient amino acid defiend high fat diet) chow for 12 weeks to model Non-alcoholic Steatohepatitis (NASH) disease in humans.
2019-05-31 | GSE120977 | GEO
Project description:Non-alcoholic steatohepatitis (NASH) is the most significant cause of chronic liver disease worldwide, with limited therapeutic options. In this experiment, a choline-deficient amino acid-defined high fat diet (CDAHFD) were used to construct a mouse NASH model. After 16 weeks of CDAHFD diets, liver samples were collected. We want to further confirm that the elevated EFHD2 is specifically expressed in infiltrated macrophages/monocytes in NASH.
2024-01-01 | GSE243079 | GEO
Project description:Choline and methionine/choline deficient diets are widely used to generate severe rodent hepatic steatosis and steatohepatitis in an attempt to reflect stages of human non-alcoholic fatty liver disease (NAFLD). The underlying mechanism of hepatic injury in these models, and how this reflects human disease remains incompletely understood. We used detailed transcriptional analysis to interrogate the molecular mechanisms of this intervention and its similarity to human disease. Adult C57Bl/6J mice were maintained on control, choline deficient (CDD) or methionine/choline deficient (MCDD) diets for 4 weeks. Isolated liver RNA was used for transcriptional profiling by micro array analysis.
2016-06-01 | E-MTAB-3943 | biostudies-arrayexpress
Project description:The TET2 gene encodes an α-ketoglutarate-dependent dioxygenase able to oxidize 5-methylcytosine into 5-hydroxymethylcytosine, which is a step toward active DNA demethylation. TET2 is frequently mutated in myeloid malignancies but also in B- and T-cell malignancies. TET2 somatic mutations are also identified in healthy elderly individuals with clonal hematopoiesis. Tet2-deficient mouse models showed widespread hematological differentiation abnormalities, including myeloid, T-cell, and B-cell malignancies. We show here that, similar to what is observed with constitutive Tet2-deficient mice, B-cell-specific Tet2 knockout leads to abnormalities in the B1-cell subset and a development of B-cell malignancies after long latency. Aging Tet2-deficient mice accumulate clonal CD19+ B220low immunoglobulin M+ B-cell populations with transplantable ability showing similarities to human chronic lymphocytic leukemia, including CD5 expression and sensitivity to ibrutinib-mediated B-cell receptor (BCR) signaling inhibition. Exome sequencing of Tet2-/- malignant B cells reveals C-to-T and G-to-A mutations that lie within single-stranded DNA-specific activation-induced deaminase (AID)/APOBEC (apolipoprotein B messenger RNA editing enzyme, catalytic polypeptide-like) cytidine deaminases targeted motif, as confirmed by the lack of a B-cell tumor in compound Tet2-Aicda-deficient mice. Finally, we show that Tet2 deficiency accelerates and exacerbates T-cell leukemia/lymphoma 1A-induced leukemogenesis. Together, our data establish that Tet2 deficiency predisposes to mature B-cell malignancies, which development might be attributed in part to AID-mediated accumulating mutations and BCR-mediated signaling. This accession concerns 46 transcriptomic experiments with Affymetrix Mouse 430-2 array..
2019-12-12 | E-MTAB-8501 | biostudies-arrayexpress
Project description:The conversion of 5-methylcytosine (5mC) into 5-Hydroxymethylcytosine (5hmC) by ten-eleven translocation (Tet) family has recently been identified as a key process for active DNA demethylation, whose effects in the immune response is currently unknown. We used microarrays to characterize the regulation of Tet2 in T cells. We found that deletion of the Tet2 gene in T cells decreased expression of effector cytokines such as IFN-?, IL-17, and IL-10. To analyze the regulation of Tet2 in Th subset differentation, CD2(Cre)Tet2(f/f) mice were used to derive Tet2-deficient Th1 and Th17 cells, and Tet2(f/f) mice were used for Tet2-enriched Th1 and Th17 cells.
2015-04-12 | E-GEOD-48657 | biostudies-arrayexpress
Project description:TET2 is one of the most frequently mutated genes in hematological malignancies. TET2 mutations are also frequently observed in healthy individuals with clonal hematopoiesis. Additional factors, such as inflammatory stress, might promote the expansion and initiate the pre-leukemic condition of Tet2 deficient hematopoietic stem cells. Antibiotics treatment is frequently used in normal individuals and patients with hematological malignancies treatment to suppress infection-induced inflammation. However, prolonged antibiotics treatment resulted in bone marrow suppression and gut microbiota alteration. In our study, we observed that the expansion of Tet2 deficient myeloid cells are positively correlated with serum cytokine levels at pre-malignant stages. We then evaluated the effect of antibiotic treatment in Tet2 deficient myeloid and lymphoid tumors in vivo. We found that antibiotics treatment suppressed the growth of Tet2 deficient malignant cells in vivo. RNA-seq analysis revealed significant changes in immune related signaling pathways (e.g., Tnf-α signaling) in antibiotics treated Tet2 deficient myeloid and lymphoid tumor cells. Suppression of Tnf-α signaling using pharmacological inhibitors partially suppressed Tet2 deficient tumor cell growth in vivo. In summary, our results suggest that the expansion of Tet2 deficient blood cells are positively associated with a pre-inflammatory condition and suppression of inflammatory pathways may attenuate the progression of TET2 inactivation-associated hematological malignancies.
2021-04-01 | GSE129886 | GEO
Project description:Ten-eleven translocation-2 (TET2) is a member of the methylcytosine dioxygenase family of enzymes implicated in cancer and in aging due to its role as a global epigenetic modifier. TET2 has a large N-terminal domain followed by a catalytic C-terminal. Previous reports have demonstrated that the catalytic domain remains active independent of the N-terminal domain. As such, the function of the N-terminus of this large protein remains poorly characterized. Here, we identify that several isoforms of the 14-3-3 family of proteins bind TET2. 14-3-3s bind TET2 when phosphorylated at serine 99 (S99). AMPK-mediated phosphorylation at S99 promotes TET2 stability and increases global DNA 5-hydroxymethylcytosine. 14-3-3s’ interaction with TET2 serves to protect S99 phosphorylation. Disruption of this interaction leads to both reduced TET2 phosphorylation and decreased protein stability. Furthermore, we identify that the protein phosphatase 2A (PP2A) can interact with TET2 and dephosphorylates S99. Collectively, our study provides novel insights into the role of the N-terminal domain in TET2 regulation. Moreover, they demonstrate the dynamic nature of TET2 protein regulation that could have therapeutic implications for disease states resulting from reduced TET2 levels and/or activity.
2020-01-13 | PXD016160 | Pride
Project description:Nonalcoholic steatohepatitis (NASH) is a progressive disorder with aberrant lipid accumulation and subsequent inflammatory and profibrotic response. Lipid reduction through cytoplasmic lipolysis might adversely worsen steatohepatitis, however, the effect of autophagic lipolysis, lipophagy, remains obscure. We engineered the adaptor protein to induce lipophagy with lipid droplet targeting signal and modified LC3 interacting region. Activating hepatocyte lipophagy obviously mitigated both steatosis and NASH pathology. Mechanistically, lipophagy promoted the excretion of lipid from liver via lysosomal exocytosis and attenuated harmful accumulation of nonesterified fatty acid. This exocytosis was dependent on Ca2+ signal unlike the lysosomal dysfunction-related exocytosis. High content compound screening identified alpelisib and digoxin, clinically-approved compounds, as effective activators of lipophagy. Administration of alpelisib or digoxin inhibited the transition to steatohepatitis in mice fed high fat with low methionine low choline diet. Given all these data, activating lipophagy may be a promising therapeutic approach to prevent NASH progression.
2023-05-15 | GSE185911 | GEO