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1.
EMBO J ; 43(8): 1445-1483, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38499786

ABSTRACT

Regulatory T (TREG) cells develop via a program orchestrated by the transcription factor forkhead box protein P3 (FOXP3). Maintenance of the TREG cell lineage relies on sustained FOXP3 transcription via a mechanism involving demethylation of cytosine-phosphate-guanine (CpG)-rich elements at conserved non-coding sequences (CNS) in the FOXP3 locus. This cytosine demethylation is catalyzed by the ten-eleven translocation (TET) family of dioxygenases, and it involves a redox reaction that uses iron (Fe) as an essential cofactor. Here, we establish that human and mouse TREG cells express Fe-regulatory genes, including that encoding ferritin heavy chain (FTH), at relatively high levels compared to conventional T helper cells. We show that FTH expression in TREG cells is essential for immune homeostasis. Mechanistically, FTH supports TET-catalyzed demethylation of CpG-rich sequences CNS1 and 2 in the FOXP3 locus, thereby promoting FOXP3 transcription and TREG cell stability. This process, which is essential for TREG lineage stability and function, limits the severity of autoimmune neuroinflammation and infectious diseases, and favors tumor progression. These findings suggest that the regulation of intracellular iron by FTH is a stable property of TREG cells that supports immune homeostasis and limits the pathological outcomes of immune-mediated inflammation.


Subject(s)
Apoferritins , T-Lymphocytes, Regulatory , Animals , Humans , Mice , Apoferritins/genetics , Apoferritins/metabolism , Cell Lineage/genetics , Cytosine/metabolism , Forkhead Transcription Factors , Iron/metabolism
2.
Int J Mol Sci ; 24(18)2023 Sep 06.
Article in English | MEDLINE | ID: mdl-37762023

ABSTRACT

Epigenetics is a rapidly developing science that has gained a lot of interest in recent years due to the correlation between characteristic epigenetic marks and cardiovascular diseases (CVDs). Epigenetic modifications contribute to a change in gene expression while maintaining the DNA sequence. The analysis of these modifications provides a thorough insight into the cardiovascular system from its development to its further functioning. Epigenetics is strongly influenced by environmental factors, including known cardiovascular risk factors such as smoking, obesity, and low physical activity. Similarly, conditions affecting the local microenvironment of cells, such as chronic inflammation, worsen the prognosis in cardiovascular diseases and additionally induce further epigenetic modifications leading to the consolidation of unfavorable cardiovascular changes. A deeper understanding of epigenetics may provide an answer to the continuing strong clinical impact of cardiovascular diseases by improving diagnostic capabilities, personalized medical approaches and the development of targeted therapeutic interventions. The aim of the study was to present selected epigenetic pathways, their significance in cardiovascular diseases, and their potential as a therapeutic target in specific medical conditions.


Subject(s)
Cardiovascular Diseases , Humans , Cardiovascular Diseases/genetics , Cardiovascular Diseases/therapy , Epigenesis, Genetic , Epigenomics , Exercise , Heart Disease Risk Factors
3.
Front Oncol ; 12: 621460, 2022.
Article in English | MEDLINE | ID: mdl-35494033

ABSTRACT

Gliomas are the most common primary malignant intracranial brain tumors. Their proliferative and invasive behavior is controlled by various epigenetic mechanisms. 5-hydroxymethylcytosine (5-hmC) is one of the epigenetic DNA modifications that employs ten-eleven translocation (TET) enzymes to its oxidation. Previous studies demonstrated altered expression of 5-hmC across gliomagenesis. However, its contribution to the initiation and progression of human gliomas still remains unknown. To characterize the expression profiles of 5-hmC and TET in human glioma samples we used the EpiJET 5-hmC and 5-mC Analysis Kit, quantitative real-time PCR, and Western blot analysis. A continuous decline of 5-hmC levels was observed in solid tissue across glioma grades. However, in glioblastoma (GBM), we documented uncommon heterogeneity in 5-hmC expression. Further analysis showed that the levels of TET proteins, but not their transcripts, may influence the 5-hmC abundance in GBM. Early tumor-related biomarkers may also be provided by the study of aberrant DNA hydroxymethylation in the blood of glioma patients. Therefore, we explored the patterns of TET transcripts in plasma samples and we found that their profiles were variously regulated, with significant value for TET2. The results of our study confirmed that DNA hydroxymethylation is an important mechanism involved in the pathogenesis of gliomas, with particular reference to glioblastoma. Heterogeneity of 5-hmC and TET proteins expression across GBM may provide novel insight into define subtype-specific patterns of hydroxymethylome, and thus help to interpret the heterogeneous outcomes of patients with the same disease.

4.
JBMR Plus ; 4(8): e10383, 2020 Aug.
Article in English | MEDLINE | ID: mdl-33134768

ABSTRACT

Skeletal development is a tightly orchestrated process in which cartilage and bone differentiation are intricately intertwined. Recent studies have highlighted the contribution of epigenetic modifications and their writers to skeletal development. Methylated cytosine (5mC) can be oxidized to 5-hydroxymethylcytosine (5hmC) by the Ten-eleven-translocation (TET) enzymes leading to demethylation. We have previously demonstrated that 5hmC is stably accumulated on lineage-specific genes that are activated during in vitro chondrogenesis in the ATDC5 chondroprogenitors. Knockdown (KD) of Tet1 via short-hairpin RNAs blocked ATDC5 chondrogenic differentiation. Here, we aimed to provide the mechanistic basis for TET1 function during ATDC5 differentiation. Transcriptomic analysis of Tet1 KD cells demonstrated that 54% of downregulated genes were SOX9 targets, suggesting a role for TET1 in mediating activation of a subset of the SOX9 target genes. Using genome-wide mapping of 5hmC during ATDC5 differentiation, we found that 5hmC is preferentially accumulated at chondrocyte-specific class II binding sites for SOX9, as compared with the tissue-agnostic class I sites. Specifically, we find that SOX9 is unable to bind to Col2a1 and Acan after Tet1 KD, despite no changes in SOX9 levels. Finally, we compared this KD scenario with the genetic loss of TET1 in the growth plate using Tet1 -/- embryos, which are approximately 10% smaller than their WT counterparts. In E17.5 Tet1 -/- embryos, loss of SOX9 target gene expression is more modest than upon Tet1 KD in vitro. Overall, our data suggest a role for TET1-mediated 5hmC deposition in partly shaping an epigenome conducive for SOX9 function. © 2020 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

5.
Anat Rec (Hoboken) ; 302(6): 954-963, 2019 06.
Article in English | MEDLINE | ID: mdl-30369084

ABSTRACT

Genomic DNA demethylation is important for mammalian embryonic development and organ function. 5-Hydroxymethylcytosine (5hmC) is considered a novel epigenetic marker. Ten-eleven translocation (TET) enzymes convert 5-methylcytosine (5mC) to 5hmC. To explore the dynamic changes of epigenetic modifications during organogenesis in the late mouse fetus, the regional distribution and histological localization of 5hmC and TET enzymes was investigated by immunohistochemical method. The liver of mouse fetus gradually matured from embryonic day (E) 12.5 to E18.5.5mC was positive in developing liver at E16.5 and E18.5. 5hmC, TET2 and TET3 were strongly positive in hepatocytes and oval cells at E18.5. The small intestinal villi were formed at E16.5. The striate border and goblet cells appeared at E18.5. 5mC was detectable from E12.5 to E18.5. 5hmC and TET2 were positive in small intestine at E12.5, E14.5, and E18.5. The alveolar was formed at E18.5. 5mC and 5hmC were detectable from E12.5 to E18.5. Only TET2 was positive in the lung of the late Kunming mouse fetus. For vertebra, mesenchymal cells formed hyaline cartilage at E15.5 and then ossify at E16.5 and E18.8. 5mC, 5hmC, and TET2 were detectable in chondrocytes and osteocytes during the late Kunming mouse fetal; TET1 expressed from E14.5 to E16.5 and TET3 expressed in bone matrix at E18.5. In summary, TET2 was strongly expressed in liver, small intestinal, lung, and vertebra in the late Kunming mouse fetus. These findings suggested that TET2 may play a more critical role than TET1 and TET3 during organogenesis in the late stage of Kunming mouse embryo. Anat Rec, 302:954-963, 2019. © 2018 Wiley Periodicals, Inc.


Subject(s)
5-Methylcytosine/analogs & derivatives , Brain/metabolism , DNA-Binding Proteins/metabolism , Fetus/metabolism , Heart/physiology , Organogenesis , Proto-Oncogene Proteins/metabolism , 5-Methylcytosine/metabolism , Animals , Brain/embryology , DNA Methylation , DNA-Binding Proteins/genetics , Dioxygenases , Epigenomics , Female , Fetus/cytology , Heart/embryology , Mice , Pregnancy , Proto-Oncogene Proteins/genetics , Spatio-Temporal Analysis
6.
Epigenomics ; 11(3): 323-335, 2019 02.
Article in English | MEDLINE | ID: mdl-30426768

ABSTRACT

AIM: Roles of DNA 5-hydroxymethylcytosine (5hmC) in myelin repair were investigated in an experimental autoimmune encephalomyelitis (EAE) mouse model via its regulation on BDNF. METHODS: DNA 5hmC level and its limiting enzymes were detected in EAE mice. RESULTS: Global 5hmC modification, Tet1 and Tet2 significantly decreased in the spinal cord tissues of EAE mice. BDNF protein and mRNA decreased and were highly associated with BDNF 5hmC. Vitamin C, a Tet co-factor, increased global DNA 5hmC and reduced the neurological deficits at least by increasing BDNF 5hmC modification and protein levels. CONCLUSION: Tet protein-mediated 5hmC modifications represent a critical target involved in EAE-induced myelin damage. Targeting epigenetic modification may be a therapeutic strategy for multiple sclerosis.


Subject(s)
DNA Methylation , Multiple Sclerosis/etiology , Multiple Sclerosis/pathology , Spinal Cord/metabolism , Spinal Cord/pathology , Animals , Autoimmune Diseases/etiology , Autoimmune Diseases/metabolism , Autoimmune Diseases/pathology , Autoimmunity , Biomarkers , Brain-Derived Neurotrophic Factor/genetics , Brain-Derived Neurotrophic Factor/metabolism , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Dioxygenases , Encephalomyelitis, Autoimmune, Experimental , Female , Genetic Association Studies , Genetic Predisposition to Disease , Mice , Multiple Sclerosis/metabolism , Promoter Regions, Genetic , Proto-Oncogene Proteins/genetics , Proto-Oncogene Proteins/metabolism
7.
Br J Nutr ; 122(5): 499-508, 2019 09 14.
Article in English | MEDLINE | ID: mdl-30157990

ABSTRACT

Obesity and particularly central obesity are the main risk factors of colon cancer. All intestinal cell populations including stem cells, their progenitors and differentiated colonocytes seem to be the origin of colorectal cancer. However, recent data support the role of differentiated cells as cancer origin especially during inflammation. Based on Yamanaka's seminal work, re-expression of few transcription factors in terminally differentiated cells creates stemness properti'es. Although these transcription factors are involved in tumorigenesis, they are epigenetically repressed in adult tissues. We proposed that obesity might regulate methylation of stemness genes in colonocytes via inflammatory signalling. Obesity-associated inflammation was analysed using Western blot analysis of phospho-IκB (inhibitor of NF-κB). Methylation-sensitive high-resolution melting analysis was performed on colonic mucosal samples of twenty obese and twenty normal-weight men to analyse promoter methylation of POU5F1 (OCT4), NANOG, MYC and CDKN2A. TNF-treated HT-29 cells were used to recapitulate the effect of NF-κB activation on stemness genes methylation. Our results showed that colonic phosphorylation of IκB, as a signal of NF-κB activation, was higher in obese subjects compared with their normal-weight counterparts. Moreover, promoter methylation of NANOG was likely to be lower in obese subjects and correlated with central obesity. HT-29 cells incubated by TNF-α showed hypomethylation of POU5F1 and MYC genes in addition to the NANOG. These results suggest that obesity-induced inflammation might be involved in the regulation of DNA methylation of oncogenic genes such as NANOG in differentiated colonocytes and thus predispose them to later oncogenic alterations.


Subject(s)
Colon/metabolism , DNA Methylation , Intestinal Mucosa/metabolism , NF-kappa B/metabolism , Nanog Homeobox Protein/genetics , Obesity/genetics , Obesity/metabolism , Adult , Case-Control Studies , Female , HT29 Cells , Humans , Male , Middle Aged , Young Adult
8.
Neuropharmacology ; 139: 13-25, 2018 09 01.
Article in English | MEDLINE | ID: mdl-29964092

ABSTRACT

Cocaine-related DNA methylation studies have primarily focused on the specific brain regions associated with drug addiction (e.g., the nucleus accumbens, NAc). To date, no studies have focused on the complex role of both DNA methylation and demethylation in the mechanisms of psychostimulant-induced addiction in the brain and peripheral tissues. Therefore, in this study, we evaluated cocaine treatment and withdrawal (animals were withdrawn from seven days of repeated injections of cocaine that caused behavioral sensitization) effects on epigenetic DNA modifiers (i.e., DNA methyltransferases, [DNMTs] and ten-eleven translocation enzymes [TETs]) in an addiction-specific brain region (NAc), a structure outside the mesolimbic dopaminergic system (cerebellum, Cer), and in peripheral blood cells (PBCs). Using a mouse behavioral sensitization model, we demonstrated that acute cocaine (AC; 0.5 h) treatment significantly decreased Dnmt1, Dnmt3a, Tet1, and Tet2 mRNA levels in the NAc and PBC, whereas at 24 h after AC treatment, Dnmt mRNA expression and enzyme activity levels were significantly increased. Acute procaine treatment caused the opposite effect on the Dnmt3a mRNA level in PBCs; this outcome suggests that the inhibition of voltage-gated sodium channels may be the mechanism that alters Dnmt expression in PBCs. Cocaine withdrawal is associated with increased expression of Dnmts in the NAc, Cer and PBCs and the decreased expression of Tet1 and Tet3 in the NAc. Additionally, cocaine withdrawal increased DNMT but decreased TET activity levels, and these changes were associated with enhanced global and selected candidate gene promoter-region DNA methylation and hydroxymethylation levels in the NAc and PBCs. Together, these data indicate that cocaine treatment and withdrawal affect the expression of epigenetic DNA modifiers in both addiction-specific brain structures and structures outside of the mesolimbic dopaminergic system and PBCs.


Subject(s)
Cocaine-Related Disorders/metabolism , Cocaine/pharmacology , Dopamine Uptake Inhibitors/pharmacology , Epigenesis, Genetic/drug effects , Animals , Blood Cells/drug effects , Blood Cells/metabolism , Cerebellum/drug effects , Cerebellum/metabolism , Cocaine-Related Disorders/genetics , DNA Modification Methylases/metabolism , Gene Expression Regulation/drug effects , Male , Mice, Inbred C57BL , Motor Activity/drug effects , Motor Activity/physiology , Nucleus Accumbens/drug effects , Nucleus Accumbens/metabolism , RNA, Messenger/metabolism , Substance Withdrawal Syndrome/genetics , Substance Withdrawal Syndrome/metabolism
9.
Genome Biol ; 19(1): 6, 2018 01 19.
Article in English | MEDLINE | ID: mdl-29351814

ABSTRACT

BACKGROUND: Endogenous retroviruses (ERVs), which are responsible for 10% of spontaneous mouse mutations, are kept under control via several epigenetic mechanisms. The H3K9 histone methyltransferase SETDB1 is essential for ERV repression in embryonic stem cells (ESCs), with DNA methylation also playing an important role. It has been suggested that SETDB1 protects ERVs from TET-dependent DNA demethylation, but the relevance of this mechanism for ERV expression remains unclear. Moreover, previous studies have been performed in primed ESCs, which are not epigenetically or transcriptionally representative of preimplantation embryos. RESULTS: We use naïve ESCs to investigate the role of SETDB1 in ERV regulation and its relationship with TET-mediated DNA demethylation. Naïve ESCs show an increased dependency on SETDB1 for ERV silencing when compared to primed ESCs, including at the highly mutagenic intracisternal A particles (IAPs). We find that in the absence of SETDB1, TET2 activates IAP elements in a catalytic-dependent manner. Surprisingly, TET2 does not drive changes in DNA methylation levels at IAPs, suggesting that it regulates these retrotransposons indirectly. Instead, SETDB1 depletion leads to a TET2-dependent loss of H4R3me2s, which is indispensable for IAP silencing during epigenetic reprogramming. CONCLUSIONS: Our results demonstrate a novel and unexpected role for SETDB1 in protecting IAPs from TET2-dependent histone arginine demethylation.


Subject(s)
DNA-Binding Proteins/metabolism , Embryonic Stem Cells/metabolism , Genes, Intracisternal A-Particle , Histone-Lysine N-Methyltransferase/physiology , Proto-Oncogene Proteins/metabolism , Animals , Cell Line , DNA/metabolism , Dioxygenases , Endogenous Retroviruses/genetics , Epigenesis, Genetic , Histone Code , Histones/metabolism , Mice
10.
Front Immunol ; 8: 291, 2017.
Article in English | MEDLINE | ID: mdl-28382035

ABSTRACT

The adaptive immune system is dependent on functionally distinct lineages of T cell antigen receptor αß-expressing T cells that differentiate from a common progenitor in the thymus. CD4+CD8+ progenitor thymocytes undergo selection following interaction with MHC class I and class II molecules bearing peptide self-antigens, giving rise to CD8+ cytotoxic and CD4+ helper or regulatory T cell lineages, respectively. The strict correspondence of CD4 and CD8 expression with distinct cellular phenotypes has made their genes useful surrogates for investigating molecular mechanisms of lineage commitment. Studies of Cd4 and Cd8 transcriptional regulation have uncovered cis-regulatory elements that are critical for mediating epigenetic modifications at distinct stages of development to establish heritable transcriptional programs. In this review, we examine the epigenetic mechanisms involved in Cd4 and Cd8 gene regulation during T cell lineage specification and highlight the features that make this an attractive system for uncovering molecular mechanisms of heritability.

11.
Genome Biol ; 17(1): 234, 2016 11 18.
Article in English | MEDLINE | ID: mdl-27863519

ABSTRACT

BACKGROUND: Ten-eleven translocation (TET) enzymes oxidise DNA methylation as part of an active demethylation pathway. Despite extensive research into the role of TETs in genome regulation, little is known about their effect on transposable elements (TEs), which make up nearly half of the mouse and human genomes. Epigenetic mechanisms controlling TEs have the potential to affect their mobility and to drive the co-adoption of TEs for the benefit of the host. RESULTS: We performed a detailed investigation of the role of TET enzymes in the regulation of TEs in mouse embryonic stem cells (ESCs). We find that TET1 and TET2 bind multiple TE classes that harbour a variety of epigenetic signatures indicative of different functional roles. TETs co-bind with pluripotency factors to enhancer-like TEs that interact with highly expressed genes in ESCs whose expression is partly maintained by TET2-mediated DNA demethylation. TETs and 5-hydroxymethylcytosine (5hmC) are also strongly enriched at the 5' UTR of full-length, evolutionarily young LINE-1 elements, a pattern that is conserved in human ESCs. TETs drive LINE-1 demethylation, but surprisingly, LINE-1s are kept repressed through additional TET-dependent activities. We find that the SIN3A co-repressive complex binds to LINE-1s, ensuring their repression in a TET1-dependent manner. CONCLUSIONS: Our data implicate TET enzymes in the evolutionary dynamics of TEs, both in the context of exaptation processes and of retrotransposition control. The dual role of TET action on LINE-1s may reflect the evolutionary battle between TEs and the host.


Subject(s)
DNA-Binding Proteins/genetics , Mouse Embryonic Stem Cells , Proto-Oncogene Proteins/genetics , Retroelements/genetics , Animals , Cell Differentiation/genetics , DNA Methylation/genetics , Dioxygenases , Epigenesis, Genetic , Gene Expression Regulation, Developmental , Humans , Long Interspersed Nucleotide Elements/genetics , Mice , Repressor Proteins/genetics , Sin3 Histone Deacetylase and Corepressor Complex
12.
Epigenetics ; 10(7): 633-42, 2015.
Article in English | MEDLINE | ID: mdl-25970091

ABSTRACT

Previous studies have reported epigenetic changes induced by environmental exposures. However, previous investigations did not distinguish 5-methylcytosine (5mC) from a similar oxidative form with opposite functions, 5-hydroxymethylcytosine (5hmC). Here, we measured blood DNA global 5mC and 5hmC by ELISA and used adjusted mixed-effects regression models to evaluate the effects of ambient PM10 and personal PM2.5 and its elemental components-black carbon (BC), aluminum (Al), calcium (Ca), potassium (K), iron (Fe), sulfur (S), silicon (Si), titanium (Ti), and zinc (Zn)-on blood global 5mC and 5hmC levels. The study was conducted in 60 truck drivers and 60 office workers in Beijing, China from The Beijing Truck Driver Air Pollution Study at 2 exams separated by one to 2 weeks. Blood 5hmC level (0.08%) was ∼83-fold lower than 5mC (6.61%). An inter-quartile range (IQR) increase in same-day PM10 was associated with increases in 5hmC of 26.1% in office workers (P = 0.004), 20.2% in truck drivers (P = 0.014), and 21.9% in all participants combined (P < 0.001). PM10 effects on 5hmC were increasingly stronger when averaged over 4, 7, and 14 d preceding assessment (up to 132.6% for the 14-d average in all participants, P < 0.001). PM10 effects were also significant after controlling for multiple testing (family-wise error rate; FWER < 0.05). 5hmC was not correlated with personal measures of PM2.5 and elemental components (FWER > 0.05). 5mC showed no correlations with PM10, PM2.5, and elemental components measures (FWER > 0.05). Our study suggests that exposure to ambient PM10 affects 5hmC over time, but not 5mC. This finding demonstrates the need to differentiate 5hmC and 5mC in environmental studies of DNA methylation.


Subject(s)
Air Pollution/adverse effects , Cytosine/analogs & derivatives , Environmental Exposure/adverse effects , Particulate Matter/toxicity , 5-Methylcytosine/blood , Adolescent , Adult , Beijing , Cytosine/blood , Female , Humans , Male , Middle Aged , Particulate Matter/chemistry , Particulate Matter/metabolism , Young Adult
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