DNA methyltransferase 3 alpha and TET methylcytosine dioxygenase 2 restrain mitochondrial DNA-mediated interferon signaling in macrophages

Cobo, Isidoro; Tanaka, Tiffany; Mangalhara, Kailash Chandra; Lana, Addison J.; Yeang, Calvin; Han, Claudia Z.; Schlachetzki, J; Challcombe, Jean; Fixsen, Bethany; Sakai, Mashito; Li, Rick Z.; Fields, Hannah; Mokrý, Michal; Tsai, Randy G.; Bejar, Rafael; Prange, K.H.M.; Winther, Menno P.J. de; Shadel, Gerald S.; Glass, Christopher K.

doi:10.1016/j.immuni.2022.06.022

Cited by 37 publications

(27 citation statements)

References 88 publications

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“…Of note, it is well established that DKD is associated with an increased risk for CVD [ 115 ]. In this context, somatic mutations, particularly in DNA methyltransferase 3 alpha and TET methylcytosine dioxygenase 2, are also implicated in the pathogenesis of both atherosclerosis and DKD, partly by a pro-inflammatory effect [ 116 , 117 ].…”

Section: Discussionmentioning

confidence: 99%

The Role of Histone Modifications in the Pathogenesis of Diabetic Kidney Disease

Kourtidou

Τζιόμαλος

2023

IJMS

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Diabetic kidney disease (DKD) is the leading cause of chronic kidney disease. The pathogenesis of DKD is multifactorial, with several molecular pathways implicated. Recent data suggest that histone modification plays an important role in the development and progression of DKD. Histone modification appears to induce oxidative stress, inflammation and fibrosis in the diabetic kidney. In the present review, we summarize the current knowledge on the association between histone modification and DKD.

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Section: Discussionmentioning

confidence: 99%

The Role of Histone Modifications in the Pathogenesis of Diabetic Kidney Disease

Kourtidou

Τζιόμαλος

2023

IJMS

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“…Mutations in the epigenetic regulatory genes DNMT3A and TET2 appear to accelerate atherosclerosis development predominantly through qualitative changes in macrophage phenotypes. [30][31][32][33] Mouse models of DNMT3A-or TET2-mutant CHIP display accelerated atherosclerosis development in the absence of differences in blood cell counts, which stems primarily from the heightened production of proinflammatory cytokines and chemokines by mutant macrophages. 30,31 In contrast, macrophages with CHIP mutations in TP53 and JAK2 accelerate atherosclerosis development through quantitative alterations in plaque macrophage numbers.…”

Section: Clonal Hematopoiesis and Atherosclerosis: Unveiling A New Ca...mentioning

confidence: 99%

Clonal Hematopoiesis and Cardiovascular Risk: Atherosclerosis, Thrombosis, and beyond

Izzi,

Fuster

2024

Hamostaseologie

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Acquired mutations that lead to clonal hematopoiesis have emerged as a new and potent risk factor for atherosclerotic cardiovascular disease and other cardiovascular conditions. Human sequencing studies and experiments in mouse models provide compelling evidence supporting that this condition, particularly when driven by specific mutated genes, contributes to the development of atherosclerosis by exacerbating inflammatory responses. The insights gained from these studies are paving the way for the development of new personalized preventive care strategies against cardiovascular disease. Furthermore, available evidence also suggests a potential relevance of these mutation in the context of thrombosis, an area requiring thorough investigation. In this review, we provide an overview of our current understanding of this emerging cardiovascular risk factor, focusing on its relationship to atherosclerosis and thrombosis.

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“…Under pathological conditions, Frequent mutations in TET genes have been reported in hematopoietic malignancy of both myeloid and lymphoid lineages (Pethusamy et al 2022). Lose-of-function mutation in the TET2 gene is deemed as one of frequently occurring genetic variations resulting in an abnormal self-renewal of hematopoietic stem cells during the development of hematopoietic malignancy (Cobo et al 2022). In approximately 20% of acute myeloid leukemia patients showing exclusive manner with TET2 mutations, TET2 enzyme is believed to be catalyzed and inactivated by d-2-hydroxyglutarate which is an oncometabolite as a result of isocitrate dehydrogenases 1 and 2 mutations (Figueroa et al 2010).…”

Section: Accepted Manuscriptmentioning

confidence: 99%

MiR-10b-5p Impairs TET2-Mediated Inhibition of PD-L1 Transcription Thus Promoting Immune Evasion and Tumor Progression in Glioblastoma

Chen

et al. 2023

Tohoku J. Exp. Med.

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Objective: Glioblastoma (GBM) is a highly aggressive primary brain tumor that shows intratumoral heterogeneity at the cellular and molecular level. Activation of programmed death receptor 1(PD-1) interaction with its ligand PD-L1 is a well-known mechanism requisite for immune evasion deployed by malignant tumors including GBM. Herein, we set out to dissect the mechanism explaining the regulation of PD-L1 gene expression in GBM. Methods:The clinical samples consisted of 37 GBM tissues and 18 normal brain tissues. GBM cell model was treated by microRNA (miRNA) inhibitor, DNA constructs, and siRNAs. Assays of CCK-8 and Transwell insert were employed to assess the survival, migratory and invasive ability of GBM cell model. The immunosuppressive factor production, T cell apoptosis, and T cell cytotoxicity to GBM cells were evaluated in the co-culture system.Results: GBM exhibited more miR-10b-5p abundance than normal at both tissue and cellular level. Suppression of miR-10b-5p weakened the ability of GBM cell model to survive, migrate, and invade, decreased the release of immunosuppressive factors, reduced T cell apoptosis, and strengthened the T cell cytotoxicity to GBM cell model. miR-10b-5p conferred a negative control of TET2 that was downregulated in GBM. The functions of miR-10b-5p on GBM cell aggressiveness and immune evasion were mediated by TET2. TET2 recruited histone deacetylases HDAC1 and HDAC2 into the PD-L1 promoter region thus inhibiting its transcription. Conclusion:The study demonstrated the importance of miR-10b-5p-mediated repression of TET2 in PD-L1-driven immune evasion and their potential for immunotherapeutic targeting in GBM.

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DNA methyltransferase 3 alpha and TET methylcytosine dioxygenase 2 restrain mitochondrial DNA-mediated interferon signaling in macrophages

Cited by 37 publications

References 88 publications

The Role of Histone Modifications in the Pathogenesis of Diabetic Kidney Disease

The Role of Histone Modifications in the Pathogenesis of Diabetic Kidney Disease

Clonal Hematopoiesis and Cardiovascular Risk: Atherosclerosis, Thrombosis, and beyond

MiR-10b-5p Impairs TET2-Mediated Inhibition of PD-L1 Transcription Thus Promoting Immune Evasion and Tumor Progression in Glioblastoma

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