Pathogen-derived glyoxylate inhibits Tet2 DNA dioxygenase to facilitate bacterial persister formation
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ABSTRACT:
PROVIDER: PRJNA1180484 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| Other | ||||
| SRR31179458_1.fastq.gz | Fastqsanger.gz | |||
| SRR31179458_2.fastq.gz | Fastqsanger.gz | |||
| SRR31179461_1.fastq.gz | Fastqsanger.gz | |||
| SRR31179461_2.fastq.gz | Fastqsanger.gz |
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Project description:Resistance, tolerance and persistence enable pathogenic bacteria to survive antibiotic treatment and are associated with an elevated risk of treatment failure and relapsing infections. The mechanism underlying bacterial antibiotic persister formation is not well understood. Here, we show that glyoxylate, a metabolite originally evolved to allow bacteria to utilize alternative carbon sources for optimal growth and pathogenicity, also serves as a signaling molecule to alter host gene expression and support persister formation. Specifically, we discovered glyoxylate interacting with TET2 DNA dioxygenase through an in-silico screen of human metabolome. We further show that Salmonella-produced glyoxylate inhibits the activity of Tet2 to suppress the expression of pro-inflammatory genes and attenuate host immune defense. Catalytic inactivation of Tet2, by genetic knock-in mutation, glyoxylate production by Salmonella, or exogenous glyoxylate treatment, facilitates bacterial persister formation in both murine and human macrophages. Conversely, stimulating TET2 with vitamin C or blocking Salmonella production of glyoxylate counters bacterial antibiotic resistance and improves the infection treatment outcomes. In conclusion, our study reveals a novel signaling function of glyoxylate in gene regulation beyond energetic and biosynthetic metabolism. Our findings also suggest that stimulating TET activity within host cells represents a potential therapeutic strategy to combat bacterial persistence.
2025-03-18 | GSE280758 | GEO
Project description:Loss-of-function TET2 mutations (TET2MT) are common in myeloid neoplasia. TET2, a DNA dioxygenase, requires 2-oxoglutarate and Fe(II) to oxidize 5-methylcytosine. TET2MT thus result in hypermethylation and transcriptional repression. Ascorbic acid (AA) increases dioxygenase activity by facilitating Fe(III)/Fe(II) redox reaction and may alleviate some biological consequences of TET2MT by restoring dioxygenase activity. Here, we report the utility of AA in the prevention of TET2MT MN, clarify the mechanistic underpinning of the TET2-AA interactions, and demonstrate that the ability of AA to restore TET2 activity in cells depends on N- and C-terminal lysine acetylation and nature of TET2MT. Consequently, pharmacologic modulation of acetyltransferases and histone deacetylases may regulate TET dioxygenase-dependent AA effects. Thus, our study highlights the contribution of factors that may enhance or attenuate AA effects on TET2 and provides a rationale for novel therapeutic approaches including combinations of AA with class I/II HDAC inhibitor or sirtuin activators in TET2MT leukemia.
2020-09-09 | PXD020550 | Pride
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:TET enzymes oxidize 5-methylcytosine (mC) in DNA, contributing to the regulation of gene transcription and genome functions. Deficiency of TET2 promotes the development of clonal hematopoiesis and various blood cancers, yet the mechanism by which TET2 mutations facilitate tumorigenesis remains to be explored. Here, we report that a subset of TET2 mutations identified in leukemia patients alter the substrate specificity of TET2 from acting on mC to thymine. This neomorphic activity results from substitutions at key residues involved in the interactions with the mC base, including Asn1387 and His1904. Recombinant human TET2 proteins harboring the mutation of these residues can catalyze the oxidation of thymine to 5-hydroxymethyluracil (hmU) and 5-formyluracil (fU). Exogenous expression of the TET2 Asn1387Thr (N1387T) mutant in transfected cells leads to hmU accumulation, with the highest level in cells lacking SMUG1-initiated base excision repair pathway. Endogenous knock-in of N1300T, the murine equivalent of N1387T, in mouse embryonic stem cells induces hmU production, causing DNA lesions and transcriptional activation of DNA damage response genes. These findings suggest that certain patient-derived TET2 mutations acquire unexpected gain-of-functions beyond an impairment in mC oxidation, and thymine oxidation by the neomorphic mutants may impose risks to genome stability, presumably contributing to malignant transformation.
2025-02-12 | GSE278366 | GEO
Project description:Oxidation of thymine by TET2 dioxygenase carrying leukemia-derived neomorphic mutations
| PRJNA1166881 | ENA
Project description:To characterize target specificity of TETi76, we performed global gene expression analyses of K562TET2+/+ and TET2-/- control cells; TETi76 mimicked expression signatures generated by the loss of TET2 in K562. The addition of Ascorbic Acid (AA), known to enhance TET-dioxygenase activity, counteracted the changes induced by TETi76. In order to study the molecular pathway of synthetic lethality by TET-dioxygenase inhibition, natural TET2-/- mutant cell line SIGM5 was treated with TET inhibitor TETi76 and global gene expression analysis was performed by RNAseq. Result demostrate a significant upregulation of TNT-α signaling and the down regulation of Interferon-α signaling. Interestingly, we also observed significant up-modulation of oxidative stress response pathway genes consistent with the inhibition of dioxygenases. In particular, TETi76 treatment induces 8-fold increase of oxidative stress sensor NQO1 a NRF2 target gene that has been shown earlier to induce pro-apoptotic cell death in cancer cells.
2020-12-03 | GSE162487 | GEO
Project description:TET2 protein is a dioxygenase that oxidizes 5-methylcytosine and is responsible for DNA demethylation. We found that a small molecule drug (3FM-dC) activates the enzyme activity of TET2. The sequencing data suggest that 3FM-dC induced global changes in DNA hydroxymethylation and gene expression.
2022-10-18 | GSE121506 | GEO
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:DNA methylation is tightly regulated throughout mammalian development and altered methylation patterns are a hallmark of cancer. The methylcytosine dioxygenase TET2 is frequently mutated in acute myeloid leukemia (AML) and has been suggested to protect CpG islands and promoters from aberrant methylation. By generating a novel mouse model of Tet2-deficient AML we show that loss of Tet2 in hematopoietic cells leads to progressive hypermethylation of active enhancer elements and altered expression of genes implicated in tumorigenesis. In contrast, CpG island and promoter methylation does not change in a Tet2-dependent manner. Furthermore, we confirm this specific enhancer hypermethylation phenotype in human AML patients. Thus, we propose that TET2 prevents leukemic transformation of hematopoietic cells by protecting enhancers from aberrant DNA methylation. Gene expression profiles from Tet2-/-;AML1-ETO and Tet2fl/fl;AML1-ETO in vitro-grown hematopoietic cells were compared using GeneChip Mouse Gene ST 2.0 Arrays (Affymetrix). Expression changes were investigated at early (passage 2) and late (passage 10) timepoints after Tet2 disruption.
2015-04-22 | E-GEOD-59586 | biostudies-arrayexpress
Project description:Ten-Eleven-Translocation-2 (Tet2) is a DNA methylcytosine dioxygenase that functions as a tumor suppressor in hematopoietic malignancies. In this study, we revealed a role for Tet2 in sustaining the immunosuppressive function of tumor-tissue myeloid cells. We found that Tet2 expression is increased in intratumoral myeloid cells both in mouse models of melanoma and in melanoma patients, and that this increased expression is dependent on an IL-1R-MyD88 pathway. Ablation of Tet2 in myeloid cells suppressed melanoma growth in vivo, and shifted the immunosuppressive gene expression program in tumor-associated macrophages to a proinflammatory one, with a concomitant reduction of the immunosuppressive function. This resulted in increased numbers of effector T cells in the tumor, and T cell depletion abolished the reduced tumor growth observed upon myeloid-specific deletion of Tet2. Our findings reveal a non-cell-intrinsic, tumor-promoting function for Tet2, and suggest that Tet2 may present a therapeutic target for the treatment of non-hematologic malignancies.
2017-08-15 | GSE98964 | GEO