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Introduction and Objectives: MicroRNA-326 is abnormally expressed in autoimmune diseases, but its roles in autoimmune hepatitis (AIH) are unknown. In this study, we aimed to investigate the effect of miR-326 on AIH and the underlying mechanism. Materials and Methods: Concanavalin A was administrated to induce AIH in mice and the expression levels of miR-326 and TET2 was evaluated by qRT-PCR and western blot, respectively. The percentages of Th17 and Treg cells were evaluated by flow cytometry and their marker proteins were determined by western blot and ELISA. The mitochondrial membrane potential (MMP) and ROS level were tested with the JC-1 kit and DCFH-DA assay. The binding relationships between miR-326 and TET2 were verified by dual-luciferase reporter assay. The liver tissues were stained by the HE staining. In vitro, AML12 cells were cocultured with mouse CD4+T cells. The expression levels of pyroptosis-related proteins were assessed by western blot. Results: Concanavalin A triggered AIH and enhanced the expression level of miR-326 in mice. It increased both Th17/Treg ratio and the levels of their marker proteins. The expression of TET2 was decreased in AIH mice. Knockdown of miR-326 could decrease the levels of pyroptosis-related proteins, the ROS level and increase MMP. In mouse CD4+T cells, miR-326 sponged TET2 to release IL-17A. Coculture of AML12 cells with isolated CD4+T cells from miR-326 knockdown AIH mice could relieve pyroptosis. Conclusions: Knockdown of miR-326 exerted anti-pyroptosis effects via suppressing TET2 and downstream NF-kB signaling to dampen AIH. We highlighted a therapeutic target in AIH. [ABSTRACT FROM AUTHOR]

The ten-eleven translocation 2 (Tet2) protein, a member of the Tet family, acts as an α-ketoglutarate- and Fe2+-dependent dioxygenase that catalyzes the iterative oxidation of 5-methylcytosine. Tet2 is widely recognized for its involvement in diverse physiological and pathological processes. Herein, we focused on Tet2 changes in stress-related disease models, behavioral changes in response to mutant forms of Tet2, and potential mechanisms underlying the involvement of Tet2 in psychiatric symptoms. This information can contribute to the comprehensive understanding of the role of Tet2 in stress-related disorders and its potential as a therapeutic target.

Allergic rhinitis (AR) is a widespread disease that is frequently comorbid with depression. However, the mechanisms and treatments for depression in AR remain underexplored. Metformin, a widely used antidiabetic drug, has shown antidepressant effects. The aim of this study was to explore the effects and potential mechanisms of metformin on depression-like behaviors in an AR mouse model. In the present study, mice were sensitized and challenged with ovalbumin (OVA) to induce AR. Results showed that mice with AR exhibited significant depression-like behavior which was attenuated by metformin. In addition, the levels of expression of synaptic plasticity markers (anti-microtubule-associated protein 2, synaptophysin, postsynaptic density protein 95), neurogenesis markers (doublecortin and Ki-67), and brain-derived neurotrophic factor were decreased in the olfactory bulb (OB) of mice with AR, while metformin ameliorated all these alterations and reduced apoptosis in the OB of these mice. Furthermore, it enhanced the phosphorylation of AMP-activated kinase (AMPK) and the levels of ten-eleven translocation 2 (TET2) and 5-hydroxymethylcytosine in the OB. In conclusion, our findings suggest that metformin might be a viable strategy for treating AR-related depression, possibly by modulating neuroplasticity, neurogenesis, apoptosis, and BDNF signaling in the OB via the AMPK/TET2 pathway. [ABSTRACT FROM AUTHOR]

Selective intrauterine growth restriction (sIUGR), which specifically occurs in monochorionic (MC) twins, usually has a poor prognosis and the underlying mechanisms are not well understood. It is an ideal model for exploring epigenetic-modified mechanisms for fetal development in MCDA twins due to eliminating the interference of different heritable backgrounds and intrauterine environments among individuals. The levels of ten-eleven translocation 2 (TET2) and its upstream and downstream targets miR-29b-3p and transforming growth factor beta 1 (TGFB1) were determined using RT‒qPCR, western blotting, and immunohistochemistry. Using TET2 overexpression and knockdown methods, we investigated the role of TET2 in trophoblast functions. The regulatory relationships among TET2, miR-29b-3p, and TGFB1 were explored by cell migration assay, invasion assay, apoptotic ratio assays, Western blot, hMeDIP-qPCR and dual-luciferase assay. A consistent upregulation of TET2 and TGFB1 was observed in the smaller placental shares compared to the larger placental shares in sIUGR. Gain-of-function studies of TET2 in trophoblasts showed decreased cell invasion and increased apoptosis, whereas loss-of-function studies of TET2 rescued this effect. Mechanistic studies revealed that miR-29b-3p and TGFB1 were the upstream factor and downstream target of TET2, respectively. Furthermore, miR-29b-3p/TET2/TGFB1-smad was identified as a unique axis that regulates trophoblast invasion, migration, and apoptosis in a DNA hydroxymethylation-dependent manner. We elucidated the functional roles of TET2 and DNA hydroxymethylation in trophoblasts and identified a novel DNA regulatory mechanism, providing a basis for further exploration of DNA epigenetic regulatory patterns in sIUGR. [Display omitted] • TET2 and TGFB1 are increased in the smaller placental shares in sIUGR. • TET2 promotes TGFB1 expression in a DNA hydroxymethylation-dependent manner. • MiR-29b-3p is the upstream factor of TET2 and decreases TET2 expression. • MiR-29b-3p/TET2/TGFB1-smad regulates trophoblast invasion, migration and apoptosis. [ABSTRACT FROM AUTHOR]

Abstract Background: DNA hypermethylation and instability due to inactivation mutations in Ten–eleven translocation 2 (TET2) is a key biomarker of hematological malignancies. This study aims at characterizing two intronic noncanonical splice‐site variants, c.3954+5_3954+8delGTTT and c.3954+5G>A. Methods: We used in silico prediction tools, reverse transcription (RT)‐PCR, and Sanger sequencing on blood/bone marrow‐derived RNA specimens to determine the aberrant splicing. Results: In silico prediction of both variants exhibited reduced splicing strength at the TET2 intron 7 splicing donor site. RT‐PCR and Sanger sequencing identified a 62‐bp deletion at the exon 7, producing a frameshift mutation, p.Cys1298*. Conclusion: This study provides functional evidence for two intronic TET2 variants that cause alternative splicing and frameshift mutation.

The prognosis of systemic lupus erythematosus (SLE) is unpredictable. This study aimed to examine the regulatory mechanism of the AHR/TET2/NT5E pathway during SLE progression. The AHR, TET2 and NT5E expression levels were examined in T regulatory cells (Tregs) of patients with SLE. The correlation of AHR, TET2 or NT5E expression levels with the immunosuppressive functions of Tregs was analysed. In patients with SLE, the number of CD4+IL2RA−FOXP3+ T cell subset was positively correlated with the SLE disease activity index value and negatively correlated with the AHR and TET2 expression levels in CD4+IL2RA+FOXP3+ Tregs. Transcriptional profiles of 79 patients with SLE obtained from the Gene Expression Omnibus database (GSE61635 dataset) revealed a significant positive correlation between the mRNA expression levels of AHR and TET2. In silico analysis predicted that the TET2 promoter comprises an AHR‐binding site. Kynurenine (KYN) promoted the binding of AHR to the TET2 promoter in Tregs of patients with SLE and Jurkat T cell lines. Furthermore, NT5E expression was significantly downregulated in Tregs of patients with SLE, which can be attributed to the dysregulation of NT5E promoter methylation status induced by downregulated TET2 activity. Furthermore, the Treg immunosuppressive activity, which is mediated through the TET2 and A2AR‐adenosine pathways, in the KYN‐treated group was approximately two‐fold higher than that in the control group. The AHR/TET2/NT5E axis mediates the Treg immunosuppressive activity. These findings provide novel insights for the development of therapeutic approaches for SLE and related autoimmune diseases. [ABSTRACT FROM AUTHOR]

Abstract Objective To explore the correlation of mutation landscape with clinical outcomes in patients with peripheral T-cell lymphoma (PTCL). Methods We retrospectively analyzed the clinicopathological and prognosis data of 53 patients with PTCL from November 2011 to December 2017. Targeted next-generation sequencing of a 659-gene panel was performed for tissues from 53 patients with PTCLs. The correlation of mutation landscape with clinical outcomes was analyzed. Results TET2 was the most frequently mutated gene (64%), followed by RHOA (43%), PCLO (23%), DNMT3A (19%), IDH2 (17%), PIEZO1 (17%) and TP53 (15%). When mutated genes were categorized into functional groups, the most common mutations were those involved in epigenetic/chromatin modification (75%), T-cell activation (74%), and the DNA repair/TP53 pathway (64%). TET2/TP53 mutations were significantly associated with positive B symptoms (P = 0.045), and elevated lactate dehydrogenase (LDH) level (P = 0.011). Moreover, TET2/TP53 mutation was a risk factor for PTCL patient survival (HR 3.574, 95% CI 1.069 − 11.941, P = 0.039). The occurrence of JAK/STAT pathway mutations in angioimmunoblastic T-cell lymphoma (AITL) patients conferred a worse progression-free survival (HR 2.366, 95% CI 0.9130–6.129, P = 0.0334). Conclusions Heterogeneous gene mutations occur in PTCL, some of which have a negative impact on the survival outcome.

Exposure to arsenic during gestation has lasting health-related effects on the developing fetus, including an increase in the risk of metabolic disease later in life. Epigenetics is a potential mechanism involved in this process. Ten-eleven translocation 2 (TET2) has been widely considered as a transferase of 5-hydroxymethylcytosine (5hmC). Here, mice were exposed, via drinking water, to arsenic or arsenic combined with ascorbic acid (AA) during gestation. For adult offspring, intrauterine arsenic exposure exhibited disorders of glucose metabolism, which are associated with DNA hydroxymethylation reprogramming of hepatic nuclear factor 4 alpha (HNF4α). Further molecular structure analysis, by SEC-UV-DAD, SEC-ICP-MS, verified that arsenic binds to the cysteine domain of TET2. Mechanistically, arsenic reduces the stability of TET2 by binding to it, resulting in the decrease of 5hmC levels in Hnf4α and subsequently inhibiting its expression. This leads to the disorders of expression of its downstream key glucose metabolism genes. Supplementation with AA blocked the reduction of TET2 and normalized the 5hmC levels of Hnf4α , thus alleviating the glucose metabolism disorders. Our study provides targets and methods for the prevention of offspring glucose metabolism abnormalities caused by intrauterine arsenic exposure. [Display omitted] • Intrauterine arsenic exposure causes disorders of glucose tolerance and insulin resistance in adult offspring. • Intrauterine arsenic exposure causes DNA hydroxymethylation reprogramming of HNF4α by reducing the TET2 levels in livers. • Arsenic reduces the stability of TET2 by binding to it. • Supplementation of AA during gestation alleviates arsenic-induced disorders of glucose metabolism in adult offspring. [ABSTRACT FROM AUTHOR]

The epigenetic modifications, such as DNA methylation and histone acetylation, play a critical role in the pathogenesis of Parkinson's disease (PD). However, the relationship between DNA methylation and histone acetylation in PD is not fully understood. Previous studies have shown that patients with PD exhibit an epigenetic and transcriptional upregulation of Ten-Eleven Translocation 2 (TET2), a member of the DNA hydroxylases family. Silence information regulator 1 (SIRT1), a nicotinamide adenine dinucleotide (NAD)-dependent histone deacetylase, also plays a critical role in PD development and might be a potential target for PD therapy. Our previous data indicated that demethylation in the Cyclin-dependent kinase inhibitor 2A (CDKN2A) promoter by the TET2 directly activated its expression, then promoted the cell cycle arrest and cell death induced by 1-methyl-4-phenyl-pyridinium ion (MPP+). In this study, we found that the enzyme activity of SIRT1 is negatively correlated with the protein level of TET2. In addition, the deacetylation of TET2 induced by SIRT1 promotes TET2 degradation via the ubiquitin–proteasome pathway. Furthermore, the activation of endogenous SIRT1 by resveratrol (RV) leads to CDKN2A DNA hypermethylation due to the decreased TET2 protein levels, which relieves the inhibitory effect on CDK4 and upregulation of pRb, allowing cell proliferation and growth. Similar effects are observed for the inhibition of endogenous TET2 enzyme activity with TET2 inhibitor. Together, we discover a new mechanism by which the SIRT1-TET2-CDKN2A pathway is involved in the pathogenesis of PD, which may provide a potential target for PD treatment.

The epigenetic modifications, such as DNA methylation and histone acetylation, play a critical role in the pathogenesis of Parkinson's disease (PD). However, the relationship between DNA methylation and histone acetylation in PD is not fully understood. Previous studies have shown that patients with PD exhibit an epigenetic and transcriptional upregulation of Ten-Eleven Translocation 2 (TET2), a member of the DNA hydroxylases family. Silence information regulator 1 (SIRT1), a nicotinamide adenine dinucleotide (NAD)-dependent histone deacetylase, also plays a critical role in PD development and might be a potential target for PD therapy. Our previous data indicated that demethylation in the Cyclin-dependent kinase inhibitor 2A (CDKN2A) promoter by the TET2 directly activated its expression, then promoted the cell cycle arrest and cell death induced by 1-methyl-4-phenyl-pyridinium ion (MPP+). In this study, we found that the enzyme activity of SIRT1 is negatively correlated with the protein level of TET2. In addition, the deacetylation of TET2 induced by SIRT1 promotes TET2 degradation via the ubiquitin–proteasome pathway. Furthermore, the activation of endogenous SIRT1 by resveratrol (RV) leads to CDKN2A DNA hypermethylation due to the decreased TET2 protein levels, which relieves the inhibitory effect on CDK4 and upregulation of pRb, allowing cell proliferation and growth. Similar effects are observed for the inhibition of endogenous TET2 enzyme activity with TET2 inhibitor. Together, we discover a new mechanism by which the SIRT1-TET2-CDKN2A pathway is involved in the pathogenesis of PD, which may provide a potential target for PD treatment. [ABSTRACT FROM AUTHOR]

Background: Metabolic associated fatty liver disease (MAFLD), characterized by hepatic lipid accumulation and fatty degeneration, is intertwined with obesity and type 2 diabetes mellitus (T2DM). Empagliflozin is a sodium-glucose cotransporter-2 inhibitor that effectively lowers blood glucose, but its effect on MAFLD and associated mechanisms are not fully understood.Methods: Eight-week-old db/db mice, an in vivo model, were administered empagliflozin or saline intragastrically. A hepatocyte steatosis model was established by inducing HL7702 cells with high glucose and palmitic acid and then treated with or without empagliflozin. The autophagy inhibitor (3-methyladenine, 3-MA) and AMP-activated protein kinase (AMPK) activator (AICAR)/inhibitor (Compound C) were used to determine the involvement of AMPK and autophagy in the regulation of lipid accumulation by empagliflozin. Ten-eleven translocation 2 (TET2) knockdown was achieved by siRNA transfection. Hepatic steatosis was evaluated by Oil Red O staining and triglyceride quantification. Immunohistochemistry, immunofluorescence, and western blot were performed to assess protein levels.Results: Empagliflozin alleviated liver steatosis in db/db mice and reduced triglyceride content and lipid accumulation in the hepatocyte steatosis model. Empagliflozin elevated autophagy, accompanied by an increase in p-AMPK and TET2. Both 3-MA and Compound C abolished the ability of empagliflozin to induce autophagy and reduce hepatic steatosis, while these effects could be recapitulated by AICAR treatment. TET2 knockdown resulted in autophagy inhibition and lipid accumulation despite empagliflozin treatment.Conclusion: Empagliflozin improves hepatic steatosis through the AMPK-TET2-autophagy pathway. The use of empagliflozin as a treatment for preventing and treating MAFLD in patients with T2DM warrants further study.

Objective: To explore the correlation of mutation landscape with clinical outcomes in patients with peripheral T-cell lymphoma (PTCL). Methods: We retrospectively analyzed the clinicopathological and prognosis data of 53 patients with PTCL from November 2011 to December 2017. Targeted next-generation sequencing of a 659-gene panel was performed for tissues from 53 patients with PTCLs. The correlation of mutation landscape with clinical outcomes was analyzed. Results: TET2 was the most frequently mutated gene (64%), followed by RHOA (43%), PCLO (23%), DNMT3A (19%), IDH2 (17%), PIEZO1 (17%) and TP53 (15%). When mutated genes were categorized into functional groups, the most common mutations were those involved in epigenetic/chromatin modification (75%), T-cell activation (74%), and the DNA repair/TP53 pathway (64%). TET2/TP53 mutations were significantly associated with positive B symptoms (P = 0.045), and elevated lactate dehydrogenase (LDH) level (P = 0.011). Moreover, TET2/TP53 mutation was a risk factor for PTCL patient survival (HR 3.574, 95% CI 1.069 − 11.941, P = 0.039). The occurrence of JAK/STAT pathway mutations in angioimmunoblastic T-cell lymphoma (AITL) patients conferred a worse progression-free survival (HR 2.366, 95% CI 0.9130–6.129, P = 0.0334). Conclusions: Heterogeneous gene mutations occur in PTCL, some of which have a negative impact on the survival outcome. [ABSTRACT FROM AUTHOR]

Inactivation of the ten-eleven translocation (TET) family members and catalyzation of 5-methylcytosine (5-mC) into 5-hydroxymethylcytosine (5-hmC) is associated with cancer initiation and progression. AMP-activated protein kinase (AMPK) is an enzyme that stabilizes TET2; however, the clinical relevance of AMPK and TET2 expression levels is currently unclear. Therefore, the present study aimed to investigate the clinical implications of AMPK/TET2 expression levels in colorectal cancer (CRC). Immunohistochemistry was used to retrospectively examine the expression levels of AMPK and TET2 in paraffin-embedded specimens obtained from 343 patients with CRC. The results demonstrated that AMPK and TET2 were highly expressed in CRC samples. No significant association was observed between the expression levels of TET2 and patient clinicopathological characteristics (age, tumor location, lymphatic, vascular and perineural invasion, Tumor-Node-Metastasis stages and differentiation); however, patients with low expression levels of TET2 more frequently presented with distant metastasis. By contrast, the expression levels of AMPK were significantly associated with lymph node and distant metastases. The survival analysis results revealed that high expression levels of TET2 were an independent predictor of favorable prognosis compared with low TET2 levels. However, no significant differences in overall survival were observed between patients with high and low expression levels of AMPK. These results described the clinical significance of AMPK/TET2 in CRC. The results of the multivariate analysis demonstrated that high expression levels of TET2 were a predictor of a favorable prognosis, whereas AMPK was not a significant factor for determining patient prognosis; therefore, further functional analysis of AMPK/TET2 expression in CRC is needed. [ABSTRACT FROM AUTHOR]

Vascular endothelial cell (VEC) inflammation induced by low shear stress plays key roles in the initiation and progression of atherosclerosis (As). Pyroptosis is a form of inflammatory programmed cell death that is critical for As. However, the effect of low shear stress on VEC pyroptosis and the underlying mechanisms were not clear. Here we show that low shear stress promoted VEC pyroptosis and reduced the expression of Ten-Eleven Translocation 2 (TET2) methylcytosine dioxygenase. Loss of TET2 resulted in the upregulation of the expression and activity of mitochondrial respiratory complex II subunit succinate dehydrogenase B (SDHB) by decreasing the recruitment of histone deacetylase 2, independent of DNA demethylation modification. The overexpression of SDHB mediated mitochondrial injury and increased the production of reactive oxygen species (ROS). The administration of ROS scavenger NAC alleviated VEC pyroptosis induced by SDHB overexpression and TET2 shRNA. These findings show that low shear stress induced endothelial cell pyroptosis through the TET2/SDHB/ROS pathway and offer new insights into As. Image 1 • Low shear stress promotes vascular endothelial cell pyroptosis through the TET2/SDHB/ROS pathway. • The higher expression of succinate dehydrogenase B contributes to mitochondrial injury and ROS production. • TET2 regulates the expression of SDHB by recruiting HDAC2, independent on DNA methylation and hydroxymethylation. [ABSTRACT FROM AUTHOR]

Background: Mutations in the genes regulating epigenetic factors such as Ten-Eleven Translocation 2 (TET2) along with other mutations are highly effective in the patient's prognosis. The aim of this study was to evaluate the prevalence of TET2 and calreticulin (CALR) mutations among myeloproliferative neoplasms (MPNs) patients to determine if there is a prognostic value for these mutations coexistence. Materials and Methods: Blood sample was collected from patients. For the evaluation of mutations, polymerase chain reaction (PCR) was performed on the patient's DNA and PCR products were subsequently sequenced. Results: No significant correlation between coexistence of TET2 and CALR mutations with complete blood count parameters in patients was seen. However, platelet count was lower in patients with TET2 and CALR mutations compared with patients with CALR mutations only. Conclusion: The coexistence of CALR and TET2 mutations in MPN patients can be used as a prognostic factor. [ABSTRACT FROM AUTHOR]

Epigenetics plays an important role in the development and progression of many diseases. There is increasing evidence for the importance of epigenetic modifications in the progression of psoriasis. The aim of this study was to examine the role and potential mechanism of action of 5-hydroxymethylcytosine (5-hmC) and ten-eleven translocation-2 (TET2) in psoriasiform dermatitis in mice. Immunohistochemical staining was performed on psoriasis patients and healthy controls. Topical application of imiquimod cream to the dorsal skin of mice was used to induce psoriasiform dermatitis. In comparison with healthy controls, 5-hmC was more extensive and intense in the skin lesions from psoriasis patients. TET2 and 5-hmC were highly expressed in imiquimod-induced psoriasiform skin lesions. Importantly, knockdown of TET2 expression in mice attenuated the psoriasiform phenotype and the expression levels of proinflammatory cytokines (interleukin- 17A and -17F and interferon-γ) and the chemokine CXCL1 in the lesional skin of mice. This is the first demonstration of a critical role for TET2 in psoriasiform dermatitis in a mouse model, and indicates that 5-hmC may serve as a potential biomarker of psoriasis. [ABSTRACT FROM AUTHOR]

The lateral habenula (LHb) has been considered a moderator of social behaviors. However, it remains unknown how LHb regulates social interaction. Here, we show that the hydroxymethylase Tet2 is highly expressed in the LHb. Tet2 conditional knockout (cKO) mice exhibit impaired social preference; however, replenishing Tet2 in the LHb rescues social preference impairment in Tet2 cKO mice. Tet2 cKO alters DNA hydroxymethylation (5hmC) modifications in genes that are related to neuronal functions, as is confirmed by miniature two-photon microscopy data. Further, Tet2 knockdown in the glutamatergic neurons of LHb causes impaired social behaviors, but the inhibition of glutamatergic excitability restores social preference. Mechanistically, we identify that Tet2 deficiency reduces 5hmC modifications on the Sh3rf2 promoter and Sh3rf2 mRNA expression. Interestingly, Sh3rf2 overexpression in the LHb rescues social preference in Tet2 cKO mice. Therefore, Tet2 in the LHb may be a potential therapeutic target for social behavior deficit-related disorders such as autism. [Display omitted] • Tet2 deficiency in the LHb results in social preference deficit • Tet2 plays an important role in regulating the activity of LHb neurons • Tet2 deficiency-induced hydroxymethylation dynamics alter neuronal activity in the LHb • Tet2 modifies 5hmC on autism-related gene Sh3rf2 to affect social preference Xu et al. show that Tet2 is highly expressed in the LHb, and Tet2 deficiency in the LHb leads to abnormal neuronal activity, resulting in social preference deficits. Mechanistically, Tet2 deficiency reduces the 5hmC modification of the promoter of the autism-related genes such as Sh3rf2 , which regulates social preference. [ABSTRACT FROM AUTHOR]

Malignant gliomas are the most common and aggressive type of brain tumor. The suppressive role of ten-eleven translocation 2 (TET2) has been implicated in certain types of cancer, however, its role in gliomas remains to be elucidated. The present study aimed to determine the expression pattern and biological role of TET2 in glioma, using RT-qPCR and immunohistochemistry, and its results indicated that the expression of TET2 was frequently decreased in gliomas and that repression of the expression of TET2 correlated with the progression of glioma. The ectopic expression of TET2 inhibited the invasive potential of glioma cells, and inhibited glioma cell proliferation in vitro and growth in vivo. Additionally, the expression of Zinc finger E-box-binding homeobox 1 (ZEB1) was increased in gliomas and was positively correlated with progression, but inversely correlated with the expression of TET2. ZEB1 was also confirmed to physically bind to the TET2 promoter. ZEB1 knockdown resulted in an increase in the expression of TET2 and elevation of TET2 promoter activity in glioma cells. These findings indicated that the downregulation of TET2 by ZEB1 is a critical oncogenic event in gliomas. [ABSTRACT FROM AUTHOR]

Purpose: DNA methylation is an important epigenetic modification that is frequently altered in cancer. Recent reports showed that the level of 5-hydroxymethylcytosine (5-hmC) was altered in various types of cancers. The influence of DNA methylation in epithelial ovarian cancer (EOC) is not fully understood. Therefore, the aim of the present study was to investigate factors involved in DNA demethylation in EOC compared with normal ovarian tissues. Methods: We examined the expression of 5-hmC, 5-mC, and TET2 by immunohistochemistry in 130 cases of EOC and 40 cases of normal ovarian tissues. We assessed the prognostic values of 5-hmC, 5-mC, and TET2 in clinical outcome of EOC. Results: We discovered a significant decrease in 5-hmC and TET2 expression in EOC compared with normal ovarian tissues. In contrast, there was a significant increase in 5-mC expression in EOC compared with normal ovarian tissues. The expression of 5-hmC, 5-mC, and TET2 correlated with pathologic stage, tumor grading, lymph node metastasis, and vascular thrombosis. Furthermore, decreased level of 5-hmC predicts poor prognosis of EOC patients. The expression of 5-hmC was an independent prognostic factor for overall survival of EOC patients. Conclusions: The data suggest that loss of 5-hmC is an epigenetic event of EOC, and the expression of 5-hmC could serve as a prognostic factor for EOC. [ABSTRACT FROM AUTHOR]

Abstract: Aberrant DNA methylation can lead to genome destabilization and to deregulated gene expression. Recently, 5-hydroxymethylcytosine (5hmC), derived from oxidation of 5-methylcytosine (5mC) by the Ten-Eleven Translocation (TET) enzymes, has been detected. 5hmC is now considered as a new epigenetic DNA modification with relevant roles in cell homeostasis regulating DNA demethylation and transcription. Our aim was to investigate possible changes in the DNA methylation/demethylation machinery in MS. We assessed the expression of enzymes involved in DNA methylation/demethylation in peripheral blood mononuclear cells (PBMCs) from 40 subjects with MS and 40 matched healthy controls. We performed also, DNA methylation analysis of specific promoters and analysis of global levels of 5mC and 5hmC. We show that TET2 and DNMT1 expression is significantly down-regulated in MS PBMCs and it is associated with aberrant methylation of their promoters. Furthermore, 5hmC is decreased in MS PBMCs, probably as a result of the diminished TET2 level. [Copyright &y& Elsevier]

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Background: Metabolic associated fatty liver disease (MAFLD), characterized by hepatic lipid accumulation and fatty degeneration, is intertwined with obesity and type 2 diabetes mellitus (T2DM). Empagliflozin is a sodium-glucose cotransporter-2 inhibitor that effectively lowers blood glucose, but its effect on MAFLD and associated mechanisms are not fully understood. Methods: Eight-week-old db/db mice, an in vivo model, were administered empagliflozin or saline intragastrically. A hepatocyte steatosis model was established by inducing HL7702 cells with high glucose and palmitic acid and then treated with or without empagliflozin. The autophagy inhibitor (3-methyladenine, 3-MA) and AMP-activated protein kinase (AMPK) activator (AICAR)/inhibitor (Compound C) were used to determine the involvement of AMPK and autophagy in the regulation of lipid accumulation by empagliflozin. Ten-eleven translocation 2 (TET2) knockdown was achieved by siRNA transfection. Hepatic steatosis was evaluated by Oil Red O staining and triglyceride quantification. Immunohistochemistry, immunofluorescence, and western blot were performed to assess protein levels. Results: Empagliflozin alleviated liver steatosis in db/db mice and reduced triglyceride content and lipid accumulation in the hepatocyte steatosis model. Empagliflozin elevated autophagy, accompanied by an increase in p -AMPK and TET2. Both 3-MA and Compound C abolished the ability of empagliflozin to induce autophagy and reduce hepatic steatosis, while these effects could be recapitulated by AICAR treatment. TET2 knockdown resulted in autophagy inhibition and lipid accumulation despite empagliflozin treatment. Conclusion: Empagliflozin improves hepatic steatosis through the AMPK-TET2-autophagy pathway. The use of empagliflozin as a treatment for preventing and treating MAFLD in patients with T2DM warrants further study. [ABSTRACT FROM AUTHOR]

Defective cholesterol efflux pathways in mice promote the expansion of hematopoietic stem and progenitor cells and a bias toward the myeloid lineage, as observed in chronic myelomonocytic leukemia (CMML). Here, we identify 5 somatic missense mutations in ABCA1 in 26 patients with CMML. These mutations confer a proliferative advantage to monocytic leukemia cell lines in vitro. In vivo inactivation of ABCA1 or expression of ABCA1 mutants in hematopoietic cells in the setting of Tet2 loss demonstrates a myelosuppressive function of ABCA1. Mechanistically, ABCA1 mutations impair the tumor-suppressor functions of WT ABCA1 in myeloproliferative neoplasms by increasing the IL-3Rβ signaling via MAPK and JAK2 and subsequent metabolic reprogramming. Overexpression of a human apolipoprotein A-1 transgene dampens myeloproliferation. These findings identify somatic mutations in ABCA1 that subvert its anti-proliferative and cholesterol efflux functions and permit the progression of myeloid neoplasms. Therapeutic increases in HDL bypass these defects and restore normal hematopoiesis. • ABCA1 somatic mutations were identified in CMML patients • ABCA1 mutations fail to repress myeloproliferative neoplasms in Tet2 -deficient mice • ABCA1 mutations sustain IL-3Rβ signaling-driven myelopoiesis in Tet2-deficient HSPCs • Overexpression of apoA-1 overcomes ABCA1 / TET2 co-mutant myeloproliferative neoplasms Viaud et al. show that ABCA1 mutants identified in CMML patients diminish the tumor-suppressor functions of ABCA1 and cooperate with Tet2 loss to confer the hypersensitivity of myeloid progenitors to IL-3 receptor β canonical signaling, which can be prevented by raising HDL levels. [ABSTRACT FROM AUTHOR]