Редактирование: DNMT1

DNA (cytosine-5)-methyltransferase 1 (EC 2.1.1.37) (Dnmt1) (CXXC-type zinc finger protein 9) (DNA methyltransferase HsaI) (DNA MTase HsaI) (M.HsaI) (MCMT) [AIM] [CXXC9] [DNMT]

==Publications==

{{medline-entry
|title=DNA Methyltransferase 1 ([[DNMT1]]) Function Is Implicated in the Age-Related Loss of Cortical Interneurons.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32793592
|abstract=Increased life expectancy in modern society comes at the cost of age-associated disabilities and diseases. Aged brains not only show reduced excitability and plasticity, but also a decline in inhibition. Age-associated defects in inhibitory circuits likely contribute to cognitive decline and age-related disorders. Molecular mechanisms that exert epigenetic control of gene expression contribute to age-associated neuronal impairments. Both DNA methylation, mediated by DNA methyltransferases (DNMTs), and histone modifications maintain neuronal function throughout lifespan. Here we provide evidence that [[DNMT1]] function is implicated in the age-related loss of cortical inhibitory interneurons. [i]Dnmt1[/i] deletion in parvalbumin-positive interneurons attenuates their age-related decline in the cerebral cortex. Moreover, conditional [i]Dnmt1[/i]-deficient mice show improved somatomotor performance and reduced aging-associated transcriptional changes. A decline in the proteostasis network, responsible for the proper degradation and removal of defective proteins, is implicated in age- and disease-related neurodegeneration. Our data suggest that [[DNMT1]] acts indirectly on interneuron survival in aged mice by modulating the proteostasis network during life-time.

|keywords=* DNA methylation
* GABA
* aging
* cerebral cortex
* inhibitory interneurons
* proteostasis
* synapse
* transcriptional control
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7387673
}}
{{medline-entry
|title=4D Genome Rewiring during Oncogene-Induced and Replicative Senescence.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32220303
|abstract=To understand the role of the extensive senescence-associated 3D genome reorganization, we generated genome-wide chromatin interaction maps, epigenome, replication-timing, whole-genome bisulfite sequencing, and gene expression profiles from cells entering replicative senescence (RS) or upon oncogene-induced senescence (OIS). We identify senescence-associated heterochromatin domains (SAHDs). Differential intra- versus inter-SAHD interactions lead to the formation of senescence-associated heterochromatin foci (SAHFs) in OIS but not in RS. This OIS-specific configuration brings active genes located in genomic regions adjacent to SAHDs in close spatial proximity and favors their expression. We also identify [[DNMT1]] as a factor that induces SAHFs by promoting [[HMGA2]] expression. Upon [[DNMT1]] depletion, OIS cells transition to a 3D genome conformation akin to that of cells in replicative senescence. These data show how multi-omics and imaging can identify critical features of RS and OIS and discover determinants of acute senescence and SAHF formation.
|mesh-terms=* Cells, Cultured
* Cellular Senescence
* Chromatin Assembly and Disassembly
* DNA (Cytosine-5-)-Methyltransferase 1
* DNA Methylation
* Fibroblasts
* Genome, Human
* Heterochromatin
* Humans
* In Situ Hybridization, Fluorescence
* Oncogenes
|keywords=* 3D genome architecture
* DNMT1
* Hi-C
* chromatin compartments
* gene regulation
* oncogene-induced senescence
* replicative senescence
* senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7208559
}}
{{medline-entry
|title=Small extracellular vesicles deliver miR-21 and miR-217 as pro-senescence effectors to endothelial cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32158519
|abstract=The role of epigenetics in endothelial cell senescence is a cutting-edge topic in ageing research. However, little is known of the relative contribution to pro-senescence signal propagation provided by microRNAs shuttled by extracellular vesicles (EVs) released from senescent cells. Analysis of microRNA and DNA methylation profiles in non-senescent (control) and senescent (SEN) human umbilical vein endothelial cells (HUVECs), and microRNA profiling of their cognate small EVs (sEVs) and large EVs demonstrated that SEN cells released a significantly greater sEV number than control cells. sEVs were enriched in miR-21-5p and miR-217, which target [[DNMT1]] and [[SIRT1]]. Treatment of control cells with SEN sEVs induced a miR-21/miR-217-related impairment of [[DNMT1]]-[[SIRT1]] expression, the reduction of proliferation markers, the acquisition of a senescent phenotype and a partial demethylation of the locus encoding for miR-21. MicroRNA profiling of sEVs from plasma of healthy subjects aged 40-100 years showed an inverse U-shaped age-related trend for miR-21-5p, consistent with senescence-associated biomarker profiles. Our findings suggest that miR-21-5p/miR-217 carried by SEN sEVs spread pro-senescence signals, affecting DNA methylation and cell replication.

|keywords=* Cellular senescence
* DNMT1
* SIRT1
* extracellular vesicles
* microRNAs
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7048230
}}
{{medline-entry
|title=Collagens and DNA methyltransferases in mare endometrosis.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31512314
|abstract=Inflammation and fibroproliferative diseases may be modulated by epigenetic changes. Therefore, we suggest that epigenetic mechanisms could be involved in equine endometrosis pathogenesis. DNA methylation is one of the methods to evaluate epigenetics, through the transcription of methyltransferases ([[DNMT1]], [[DNMT3A]], [[DNMT3B]]). The correlation between DNMTs and collagen (COL) transcripts was assessed for the different Kenney and Doig's (Current Therapy in Theriogenology. Philadelphia: WB Saunders; 1986) endometrium categories. Endometrial biopsies were randomly collected from cyclic mares. Histological classification (category I, n = 13; II A, n = 17; II B, n = 12; and III, n = 7) and evaluation of [[COL1A2]], [[COL3A1]] and DNMTs transcripts by qPCR, were performed. Data were analysed by one-way analysis of variance (ANOVA), Kruskal-Wallis test and Pearson correlation. As mares aged, there was an increase in endometrium fibrosis (p < .01), and in [[DNMT1]] mRNA (p < .001). Considering [[DNMT3B]] transcripts for each category, there was an increase with fibrosis (p < .05). No changes were observed for [[DNMT1]] and [[DNMT3A]] transcripts. However, [[DNMT3A]] mRNA levels were the highest in all categories (p < .01). In category I endometrium, a positive correlation was observed for transcripts of all DNMTs in both COLs (p < .01). In category IIA, this correlation was also maintained for all DNMTs transcripts in [[COL1A2]] (p < .05), but only for [[DNMT3B]] in [[COL3A1]] (p < .05). In category IIB, there was a positive correlation between [[DNMT3B]] and [[COL3A1]] (p < .05). In category III, a positive correlation was only observed between [[DNMT3B]] and [[COL3A1]] (p < .05). Our results suggest that there is a disturbance in COLs and DNMTs correlation during fibrosis.
|mesh-terms=* Aging
* Animals
* Collagen
* DNA (Cytosine-5-)-Methyltransferases
* DNA Methylation
* Endometritis
* Endometrium
* Female
* Fibrosis
* Horse Diseases
* Horses
* RNA, Messenger
|keywords=* DNA methylation
* collagen
* endometrium
* epigenetic
* fibrosis
* mare
|full-text-url=https://sci-hub.do/10.1111/rda.13515
}}
{{medline-entry
|title=Mechanism of [[SPRY1]] methylation regulating natural aging of skin epidermal cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31483543
|abstract=To investigate the relationship among natural aging of epidermal cells, epigenetics, and [[SPRY1]] methylation mechanism. Immunohistochemistry, reverse transcription-PCR (RT-PCR), and Western blot were used to detect the expression of DNA methyltransferase 1 ([[DNMT1]]) and Sprouty1 ([[SPRY1]]) in skin epithelial cells from different age groups. An aging model of HaCaT cells was constructed. In HaCaT cells and their aging groups, [[DNMT1]] and [[SPRY1]] expression were detected by RT-PCR and WB. [[SPRY1]] methylation status in epidermal cells from different age groups and HaCaT cells were detected by Methylation-Specific PCR (MS-PCR). The expression of [[DNMT1]] and [[SPRY1]] in skin epithelial cells from natural aging groups decreased with age; there was no significant difference in the expression of [[DNMT1]] in HaCaT cells and the different age groups. The expression of [[SPRY1]] in HaCaT cells was lower than it was in the aging groups. The methylation status of [[SPRY1]] gradually decreased as the age of skin epidermal cells increased, while the methylation status of [[SPRY1]] was not different between HaCaT cells and the aging group. [[DNMT1]] is involved in the regulation of natural aging of skin epidermal cells but has a nominal role in our induced aging model. [[SPRY1]] is involved in natural aging and induced aging of skin epidermal cells. The regulation of [[SPRY1]] methylation is involved in the natural senescence of skin epidermal cells, while the induced aging of epidermal cells is nominally involved in the mechanism of [[SPRY1]] methylation.

|keywords=* SPRY1
* methylation
* natural aging
* skin epidermal aging
|full-text-url=https://sci-hub.do/10.1111/jocd.13126
}}
{{medline-entry
|title=Age-related Changes in the Global DNA Methylation Profile of Oligodendrocyte Progenitor Cells Derived from Rat Spinal Cords.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30868493
|abstract=Demyelination of axons plays an important role in the pathology of many spinal cord diseases and injuries. Remyelination in demyelinated lesions is primarily performed by oligodendrocyte progenitor cells (OPCs), which generate oligodendrocytes in the developing and mature central nervous system. The efficiency of remyelination decreases with age. Many reports suggest that this decline in remyelination results from impaired OPC recruitment and differentiation during aging. Of the various molecular mechanisms involved in aging, changes in epigenetic modifications have received particular attention. Global DNA methylation is a major epigenetic modification that plays important roles in cellular senescence and organismal aging. Thus, we aimed to evaluate the dynamic changes in the global DNA methylation profiles of OPCs derived from rat spinal cords during the aging process. We separated and cultured OPCs from the spinal cords of neonatal, 4-month-old, and 16-month-old rats and investigated the age-related alterations of genomic DNA methylation levels by using quantitative colorimetric analysis. To determine the potential cause of dynamic changes in global DNA methylation, we further analyzed the activity of DNA methyltransferases (DNMTs) and the expression of [[DNMT1]], DNMT3a, DNMT3b, [[TET1]], [[TET2]], [[TET3]], [[MBD2]], and MeCP2 in the OPCs from each group. Our results showed the genomic DNA methylation level and the activity of DNMTs from OPCs derived from rat spinal cords decreased gradually during aging, and OPCs from 16-month-old rats were characterized by global hypomethylation. During OPC aging, the mRNA and protein expression levels of DNMT3a, DNMT3b, and MeCP2 were significantly elevated; those of [[DNMT1]] were significantly down-regulated; and no significant changes were observed in those for [[TET1]], [[TET2]], [[TET3]], or [[MBD2]]. Our results indicated that global DNA hypomethylation in aged OPCs is correlated with [[DNMT1]] downregulation. Together, these data provide important evidence for partly elucidating the mechanism of age-related impaired OPC recruitment and differentiation and assist in the development of new treatments for promoting efficient remyelination.
|mesh-terms=* Aging
* Animals
* Animals, Newborn
* Cell Differentiation
* Cells, Cultured
* DNA Methylation
* DNA-Cytosine Methylases
* Epigenesis, Genetic
* Gene Expression Regulation
* Oligodendrocyte Precursor Cells
* Rats
* Spinal Cord
|keywords=* Duchenne muscular dystrophy
* T2 mapping
* fat infiltration
* skeletal muscle
|full-text-url=https://sci-hub.do/10.1007/s11596-019-2001-y
}}
{{medline-entry
|title=Epigallocatechin-3-gallate and BIX-01294 have different impact on epigenetics and senescence modulation in acute and chronic myeloid leukemia cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30194939
|abstract=Myeloid leukemia treatment is quite successful nowadays; nevertheless the development of new therapies is still necessary. In the present study, we investigated the potential of epigenetic modulators EGCG (epigallocatechin-3-gallate) and BIX-01294 (N-(1-benzylpiperidin-4-yl)-6,7-dimethoxy-2-(4-methyl-1,4-diazepan-1-yl)quinazolin-4-amine) to alter epigenetic state and cause cellular senescence in acute and chronic myeloid leukemia NB4 and K562 cells. We have shown that after leukemia cell treatment with EGCG and BIX-01294 the proliferation and survival were inhibited of both cell lines; however, only NB4 cells underwent apoptosis. Both epigenetic modulators caused cell cycle arrest in G0/G1 phase as assessed by RT-qPCR (p53, p21, Rb) and flow cytometry analysis. Increased levels of [[ATM]], [[HMGA2]], phosphorylated [[ATM]], and SA-β-galactosidase staining indicated that EGCG caused cellular senescence, whereas BIX-01294 did not. Immunoblot analysis of epigenetic players [[DNMT1]], HP1α, H3K9me3, [[EZH2]], and [[SUZ12]] demonstrated beneficial epigenetic modulation by both agents with exception of mainly no epigenetic changes caused in K562 cells by EGCG. Therefore, we suggest EGCG as a promising epigenetic modulator for acute promyelocytic leukemia therapy and as a potential cellular senescence inducer in both acute and chronic myeloid leukemia treatment, whereas BIX-01294 could be beneficial as an epigenetic modifier for both myeloid leukemias treatment.
|mesh-terms=* Antineoplastic Agents
* Azepines
* Catechin
* Cellular Senescence
* Drug Screening Assays, Antitumor
* Epigenesis, Genetic
* G1 Phase Cell Cycle Checkpoints
* Gene Expression Regulation, Neoplastic
* Humans
* K562 Cells
* Leukemia, Myelogenous, Chronic, BCR-ABL Positive
* Leukemia, Promyelocytic, Acute
* Quinazolines
|keywords=* BIX-01294
* EGCG
* Epigenetic regulation
* Myeloid leukemia
* Senescence
|full-text-url=https://sci-hub.do/10.1016/j.ejphar.2018.09.005
}}
{{medline-entry
|title=Resveratrol promotes oxidative stress to drive [[DLC1]] mediated cellular senescence in cancer cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29964052
|abstract=Induction of cellular senescence represents a novel strategy to inhibit aberrant proliferation of cancer cells. Resveratrol is gaining attention for its cancer preventive and suppressive properties. Tumor suppressor gene [[DLC1]] is shown to induce apoptosis, suppress migration and invasion in various cancer cells. However, the function of [[DLC1]] in cancer cellular senescence is unclear. This study was designed to investigate the biological role of [[DLC1]] in resveratrol induced cancer cellular senescence. Our results showed that resveratrol inhibited proliferation of cancer cell lines (MCF-7, MDA-[[MB]]-231 and H1299) and induced senescence along with increase of SA-β-gal activity and regulation of senescence-associated molecular markers p38MAPK, p-p38MAPK, p27, p21, Rb and p-Rb protein. The underlying mechanism was that resveratrol induced mitochondrial dysfunction with reduction of mitochondrial membrane potential, down-regulation of MT-ND1, MT-ND6 and ATPase8 in transcript level and down-regulation of [[PGC]]-1α in protein level to result in ROS production. With ROS elevation, resveratrol decreased [[DNMT1]] and increased [[DLC1]] expression significantly. However, after ROS scavenger NAC was added to the cancer cells treated by resveratrol, [[DNMT1]], [[DLC1]] and senescence-associated molecular markers were reversed. This reveals that resveratrol induced cancer cellular senescence through [[DLC1]] in a ROS-dependent manner. Silencing [[DLC1]] markedly attenuated SA-β-gal activity and p38MAPK, p27 and p21 protein levels, and increased Rb expression, indicating that resveratrol promoted senescence via targeting [[DLC1]]. Moreover, [[DLC1]] promoted senescence through FoxO3a/NF-κB signaling mediated by [[SIRT1]] after resveratrol treatment. Finally, resveratrol increased ROS production to induce DNA damage with p-CHK1 up-regulation and result in cancer cellular senescence. This is the first time to investigate resveratrol induced cancer cellular senescence by primarily targeting [[DLC1]]. Induction of cellular senescence by resveratrol may represent a novel anticancer mechanism.
|mesh-terms=* Cellular Senescence
* DNA Damage
* GTPase-Activating Proteins
* Genes, Mitochondrial
* Humans
* Oxidative Stress
* Reactive Oxygen Species
* Resveratrol
* Signal Transduction
* Tumor Suppressor Proteins
* p38 Mitogen-Activated Protein Kinases
|keywords=* Cellular senescence
* DLC1
* Mitochondrial dysfunction
* Reactive oxygen species
* Resveratrol
* SIRT1
|full-text-url=https://sci-hub.do/10.1016/j.yexcr.2018.06.031
}}
{{medline-entry
|title=Ultraviolet A irradiation induces senescence in human dermal fibroblasts by down-regulating [[DNMT1]] via [[ZEB1]].
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29466247
|abstract=In this study, we report the role of DNA methyltransferase 1 ([[DNMT1]]) in ultraviolet A (UVA)-induced senescence in human dermal fibroblasts (HDFs). We show that [[DNMT1]] expression was significantly reduced during UVA-induced senescence, and this senescence could be alleviated or aggravated by the up- or down-regulation of [[DNMT1]], respectively. Expression of the transcription factor zinc finger E-box binding homeobox 1([[ZEB1]]) also decreased after UVA irradiation, following a UVA-induced increase of intracellular reactive oxygen species (ROS). We show that [[ZEB1]] binds to the DMNT1 promoter and regulates its transcription, which, in turn, affects cellular senescence. These changes in DMNT1 and [[ZEB1]] expression following UVA exposure were confirmed in matched skin specimens that had or had not been sun-exposed. On analyzing the promoter methylation of 24 senescence associated genes in these matched skin specimens, we discovered that p53 promoter methylation was significantly reduced in sun-exposed skin. [i]In vitro[/i] experiments confirmed that UVA irradiation reduced p53 promoter methylation, and [[DNMT1]] up-regulation could reverse this effect. Collectively, down-regulation of [[ZEB1]] caused by UVA induced ROS could transcriptionally inhibit [[DNMT1]], leading to low methylation level of senescence related proteins p53 and increase its expression, eventually result in cellar senescence.
|mesh-terms=* Cellular Senescence
* Down-Regulation
* Fibroblasts
* Humans
* Reactive Oxygen Species
* Repressor Proteins
* Skin Aging
* Skin Physiological Phenomena
* Tumor Suppressor Protein p53
* Ultraviolet Rays
* Up-Regulation
* Zinc Finger E-box-Binding Homeobox 1
|keywords=* DNMT1
* UVA
* ZEB1
* methylation
* senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5842848
}}
{{medline-entry
|title=Microrna-217 modulates human skin fibroblast senescence by directly targeting DNA methyltransferase 1.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28380423
|abstract=DNA methyltransferase 1 ([[DNMT1]]) is a major epigenetic regulator associated with many biological processes. However, the roles and mechanisms of [[DNMT1]] in skin aging are incompletely understood. Here we explored the role of [[DNMT1]] in human skin fibroblasts senescence and its related regulatory mechanisms. [[DNMT1]] expression decreased in passage-aged fibroblasts and [[DNMT1]] silencing in young fibroblasts induced the senescence phenotype. MiR-217 is predicted to target [[DNMT1]] mRNA and miR-217 expression increased in passage-aged fibroblasts. MiR-217 directly targeted the 3'-untranslated region (3'-UTR) of [[DNMT1]] in HEK 293T cells and inhibited [[DNMT1]] expression in fibroblasts. MiR-217 overexpression induced a senescence phenotype in young fibroblasts, and miR-217 downregulation in old HSFs partially reversed the senescence phenotype. However, these effects could be significantly rescued by regulating [[DNMT1]] expression in fibroblasts. After regulating miR-217 levels, we analyzed changes in the promoter methylation levels of 24 senescent-associated genes, finding that 6 genes were significantly altered, and verified p16 and phosphorylated retinoblastoma (pRb) protein levels. Finally, an inverse correlation between [[DNMT1]] and miR-217 expression was observed in skin tissues and different-aged fibroblasts. Together, these findings revealed that miR-217 promotes fibroblasts senescence by suppressing [[DNMT1]]-mediated methylation of p16 and pRb by targeting the [[DNMT1]] 3'-UTR.
|mesh-terms=* 3' Untranslated Regions
* Age Factors
* Aged
* Cell Line
* Cellular Senescence
* Child
* Child, Preschool
* Cyclin-Dependent Kinase Inhibitor p16
* DNA (Cytosine-5-)-Methyltransferase 1
* DNA Methylation
* Fibroblasts
* Gene Expression Regulation
* Gene Silencing
* Genes, Retinoblastoma
* Humans
* Infant
* Infant, Newborn
* MicroRNAs
* Promoter Regions, Genetic
* RNA Interference
* Skin
|keywords=* DNMT1
* miR-217
* senescence
* skin aging
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5464883
}}
{{medline-entry
|title=A positive feedback loop between Pim-1 kinase and [[HBP1]] transcription factor contributes to hydrogen peroxide-induced premature senescence and apoptosis.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28348080
|abstract=Oxidative stress can induce cell dysfunction and lead to a broad range of degenerative alterations, including carcinogenesis, aging, and other oxidative stress-related conditions. To avoid undergoing carcinogenesis in response to oxidative stress, cells trigger a succession of checkpoint responses, including premature senescence and apoptosis. Increasing evidence indicates that H O , an important cause of oxidative stress, functions as an important physiological regulator of intracellular signaling pathways that participate in regulation of cell premature senescence and apoptosis. However, the precise mechanisms underlying this process remain to be studied extensively. In this study, we describe the importance of Pim-1 kinase in this checkpoint response to oxidative stress. Pim-1 binds to and phosphorylates the transcription factor high mobility group box transcription factor 1 ([[HBP1]]), activating it. H O  enhances the interaction between Pim-1 and [[HBP1]] and promotes [[HBP1]] accumulation. In turn, [[HBP1]] rapidly and selectively up-regulates Pim-1 expression in H O -stimulated cells, thereby creating a Pim-1-[[HBP1]] positive feedback loop that regulates H O -induced premature senescence and apoptosis. Furthermore, the Pim-1-[[HBP1]] positive feedback loop exerts its effect by regulating the senescence markers [[DNMT1]] and p16 and the apoptosis marker Bax. The Pim-1-[[HBP1]] axis thus constitutes a novel checkpoint pathway critical for the inhibition of tumorigenesis.
|mesh-terms=* Apoptosis
* Cell Cycle Checkpoints
* Cellular Senescence
* Cyclin-Dependent Kinase Inhibitor p16
* DNA (Cytosine-5-)-Methyltransferase 1
* DNA (Cytosine-5-)-Methyltransferases
* Gene Expression Regulation, Enzymologic
* HeLa Cells
* High Mobility Group Proteins
* Humans
* Hydrogen Peroxide
* Oxidative Stress
* Proto-Oncogene Proteins c-pim-1
* Repressor Proteins
* Up-Regulation
|keywords=* HBP1
* Pim-1
* apoptosis
* cellular senescence
* gene transcription
* hydrogen peroxide
* phosphorylation
* positive feedback loop
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5437229
}}
{{medline-entry
|title=miR-377 induces senescence in human skin fibroblasts by targeting DNA methyltransferase 1.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28277545
|abstract=Skin aging is a complicated physiological process and epigenetic feature, including microRNA-mediated regulation and DNA methylation, have been shown to contribute to this process. DNA methylation is regulated by DNA methyltransferase, of which DNA methyltransferase 1 ([[DNMT1]]) is the most abundantly known. But evidence supporting its role in skin aging remains scarce, and no report regards its specifical upstream-regulating molecules in the process of skin aging so far. Here, we found that [[DNMT1]] expression was markedly higher in young human skin fibroblasts (HSFs) than that in passage-aged HSFs, and [[DNMT1]] knockdown significantly induced the senescence phenotype in young HSFs. We predicted the upstream miRNAs which could regulate [[DNMT1]] with miRNA databases and found miR-377 had high homology with a sequence in the 3'-UTR of human [[DNMT1]] mRNA. We confirmed that miR-377 was a potential regulator of [[DNMT1]] by luciferase reporter assays. miR-377 expression in passage-aged HSFs was markedly higher than that in the young HSFs. miR-377 overexpression promoted senescence in young HSFs, and inhibition of miR-377 reduced senescence in passage-aged HSFs. Moreover, these functions were mediated by targeting [[DNMT1]]. Microfluidic PCR and next-generation bisulfite sequencing of 24 senescent-associated genes' promoters revealed alterations of the promoter methylation levels of FoxD3, p53, and [[UTF1]] in HSFs treated with miR-377 mimics or inhibitors. We also verified that the miR-377-mediated changes in p53 expression could be reversed by regulation of [[DNMT1]] in HSFs. Similarly, there was a negative correlation between miR-377 and [[DNMT1]] expression in young and photoaged HSFs, HSFs, or skin tissues from UV-unexposed areas of different aged donors. Our results highlight a novel role for miR-377-[[DNMT1]]-p53 axis in HSF senescence. These findings shed new light on the mechanisms of skin aging and identify future opportunities for its therapeutic prevention.
|mesh-terms=* Aging
* DNA (Cytosine-5-)-Methyltransferase 1
* DNA (Cytosine-5-)-Methyltransferases
* DNA Methylation
* Fibroblasts
* Gene Expression Regulation
* Gene Knockdown Techniques
* High-Throughput Nucleotide Sequencing
* Humans
* MicroRNAs
* Promoter Regions, Genetic
* Skin
* Tumor Suppressor Protein p53

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5386568
}}
{{medline-entry
|title=Converting Adult Pancreatic Islet α Cells into β Cells by Targeting Both Dnmt1 and Arx.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28215845
|abstract=Insulin-producing pancreatic β cells in mice can slowly regenerate from glucagon-producing α cells in settings like β cell loss, but the basis of this conversion is unknown. Moreover, it remains unclear if this intra-islet cell conversion is relevant to diseases like type 1 diabetes (T1D). We show that the α cell regulators Aristaless-related homeobox (Arx) and DNA methyltransferase 1 (Dnmt1) maintain α cell identity in mice. Within 3 months of Dnmt1 and Arx loss, lineage tracing and single-cell RNA sequencing revealed extensive α cell conversion into progeny resembling native β cells. Physiological studies demonstrated that converted α cells acquire hallmark β cell electrophysiology and show glucose-stimulated insulin secretion. In T1D patients, subsets of glucagon-expressing cells show loss of [[DNMT1]] and [[ARX]] and produce insulin and other β cell factors, suggesting that [[DNMT1]] and [[ARX]] maintain α cell identity in humans. Our work reveals pathways regulated by Arx and Dnmt1 that are sufficient for achieving targeted generation of β cells from adult pancreatic α cells.
|mesh-terms=* Adult
* Aging
* Calcium Signaling
* Cell Lineage
* Child
* Child, Preschool
* DNA (Cytosine-5-)-Methyltransferase 1
* DNA (Cytosine-5-)-Methyltransferases
* Diabetes Mellitus, Type 1
* Electrophysiological Phenomena
* Female
* Gene Deletion
* Gene Expression Regulation
* Glucagon
* Glucagon-Secreting Cells
* Glucose
* Homeodomain Proteins
* Humans
* Insulin
* Insulin Secretion
* Insulin-Secreting Cells
* Male
* Sequence Analysis, RNA
* Single-Cell Analysis
* Transcription Factors
* Young Adult

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5358097
}}
{{medline-entry
|title=The Ubiquitin-like with PHD and Ring Finger Domains 1 ([[UHRF1]])/DNA Methyltransferase 1 ([[DNMT1]]) Axis Is a Primary Regulator of Cell Senescence.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28100769
|abstract=As senescence develops, cells sequentially acquire diverse senescent phenotypes along with simultaneous multistage gene reprogramming. It remains unclear what acts as the key regulator of the collective changes in gene expression at initiation of senescent reprogramming. Here we analyzed time series gene expression profiles obtained in two different senescence models in human diploid fibroblasts: replicative senescence and H O -induced senescence. Our results demonstrate that suppression of DNA methyltransferase 1 ([[DNMT1]])-mediated DNA methylation activity was an initial event prior to the display of senescent phenotypes. We identified seven [[DNMT1]]-interacting proteins, ubiquitin-like with PHD and ring finger domains 1 ([[UHRF1]]), [[EZH2]], [[CHEK1]], [[SUV39H1]], [[CBX5]], [[PARP1]], and [[HELLS]] (also known as LSH (lymphoid-specific helicase) 1), as being commonly down-regulated at the same time point as [[DNMT1]] in both senescence models. Knockdown experiments revealed that, among the [[DNMT1]]-interacting proteins, only [[UHRF1]] knockdown suppressed [[DNMT1]] transcription. However, [[UHRF1]] overexpression alone did not induce [[DNMT1]] expression, indicating that [[UHRF1]] was essential but not sufficient for [[DNMT1]] transcription. Although [[UHRF1]] knockdown effectively induced senescence, this was significantly attenuated by [[DNMT1]] overexpression, clearly implicating the [[UHRF1]]/[[DNMT1]] axis in senescence. Bioinformatics analysis further identified [[WNT5A]] as a downstream effector of [[UHRF1]]/[[DNMT1]]-mediated senescence. Senescence-associated hypomethylation was found at base pairs -1569 to -1363 from the transcription start site of the [[WNT5A]] gene in senescent human diploid fibroblasts. As expected, [[WNT5A]] overexpression induced senescent phenotypes. Overall, our results indicate that decreased [[UHRF1]] expression is a key initial event in the suppression of [[DNMT1]]-mediated DNA methylation and in the consequent induction of senescence via increasing [[WNT5A]] expression.
|mesh-terms=* CCAAT-Enhancer-Binding Proteins
* Cellular Senescence
* DNA (Cytosine-5-)-Methyltransferase 1
* DNA (Cytosine-5-)-Methyltransferases
* DNA Methylation
* Fibroblasts
* Gene Expression Profiling
* Gene Expression Regulation
* HEK293 Cells
* Histones
* Humans
* Hydrogen Peroxide
* Male
* Oligonucleotide Array Sequence Analysis
* Phenotype
* Promoter Regions, Genetic
* Protein Binding
* Protein Domains
* RNA, Small Interfering
* Ubiquitin-Protein Ligases
* Wnt-5a Protein
* beta-Galactosidase
|keywords=* DNA methylation
* cellular senescence
* gene expression
* gene regulation
* microarray
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5339756
}}
{{medline-entry
|title=Short term methionine restriction increases hepatic global DNA methylation in adult but not young male C57BL/6J mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/27940170
|abstract=Despite well-documented evidence for lifespan extension by methionine restriction (MR), underlying mechanisms remain unknown. As methionine can alter S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH), the substrate and product of DNA methyltransferase-1 ([[DNMT1]]), we hypothesized that MR diet alters DNA methylation. Young (8-week-old) and adult (1-year-old) male C57BL/6J mice were fed diets with different levels of methionine (0.12%-MR, 0.84%-CD) for 12weeks. Functional indicators of DNA methylation, including global methylation (GM), gene-specific methylation (GSM) and LINE-1 methylation; and biochemical factors affecting DNA methylation, SAH, SAM, and [[DNMT1]] were assessed in different tissues. MR altered DNA methylation depending on the age of intervention. While MR had no effect on hepatic GM in young animals, it increased GM by 27% over CD in adults (p<0.01). In comparison with young animals, hepatic GM levels were 17% lower in CD adults (p<0.05), but not different in MR adults. The MR-induced increase in hepatic GM was associated with a 38% decrease in SAH levels in adults (p<0.001), with SAH and GM levels being negatively correlated (r =0.33, p<0.001). No changes were observed in DNMT protein levels in liver. In adipose tissue, MR caused a 6% decline in GM in adults (p<0.05), a corresponding 2-fold increase in SAH (p<0.05), and a 2-fold decrease in [[DNMT1]] (p<0.01). MR caused both increases and decreases in GSM of liver and adipose. No changes were observed in LINE-1. Together, these findings provide evidence for protective effects of MR diet on hepatic DNA hypomethylation in adults, apparently mediated by SAH. These findings also indicate that altered DNA methylation might be playing a role in benefits conferred by MR diet.
|mesh-terms=* Aging
* Animals
* Caloric Restriction
* DNA Methylation
* Diet
* Liver
* Male
* Methionine
* Mice
* Mice, Inbred C57BL
* Time Factors
|keywords=* Aging
* Caloric restriction
* DNA methylation
* Methionine
* One-carbon cycle
* Sulfur amino acids
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5906125
}}
{{medline-entry
|title=In vivo and in silico studies to identify mechanisms associated with Nurr1 modulation following early life exposure to permethrin in rats.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/27826104
|abstract=The present work was designed to study the mechanisms associated with Nurr1 modulation following early life permethrin (PERM) treatment during rat's life span. Here we demonstrate that PERM exposure in rats, at a dose close to No Observed Adverse Effect Level (NOAEL) for 15days during neonatal brain development leads to its accumulation long after exposure. In striatum from adolescent rats we detected an increase in DNA methyltransferases (DNMTs) such as [[DNMT1]], DNMT3a, Tyrosine hydroxylase, monomeric and aggregated α-synuclein protein levels. Adult rats showed enhanced DNMT3b and α-synuclein aggregation compared to the control group, while with aging a significant decrease in all biomarkers studied was observed. No changes in Nurr1 promoter methylation in adolescent, adult and old rats were found. In silico studies showed clear evidence of a strong binding interaction between PERM and its metabolite 3-phenoxybenzoic acid with the nuclear orphan receptor Nurr1. These findings suggest that an additional interference with the dopaminergic neuron pathway could occur in situ during PERM accumulation in brain. Therefore, Nurr1 modulation in early life PERM-treated rats, depends on age-related adaptive responses in animals.
|mesh-terms=* Aging
* Animals
* Benzoates
* Binding Sites
* Corpus Striatum
* DNA Methylation
* DNA Modification Methylases
* Male
* Molecular Docking Simulation
* Molecular Dynamics Simulation
* Nuclear Receptor Subfamily 4, Group A, Member 2
* Permethrin
* Promoter Regions, Genetic
* Protein Multimerization
* Rats, Wistar
* alpha-Synuclein
|keywords=* DNMTs
* Nurr1 promoter methylation
* early life permethrin exposure
* molecular docking
* rat
* α-synuclein
|full-text-url=https://sci-hub.do/10.1016/j.neuroscience.2016.10.071
}}
{{medline-entry
|title=Age-Related Changes in DNA Methylation Associated with Shifting Th1/Th2 Balance.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/27650651
|abstract=This study was conducted in order to explore age-related changes in the production of Th1 and Th2 cytokines and determine the corresponding status of DNA methylation. The plasma IL-4 and IFN-γ levels and expression of Th-related cytokines and transcription factors in CD4  splenocytes were observed in mice at different weeks of age. The DNA methylation levels of IL-4 and IFN-γ promoters and the related regulatory regions in CD4  splenocytes of mice at different weeks of age were analyzed. The DNA methyltransferase (DNMT) levels in CD4  splenocytes of mice were analyzed. Changes in plasma IL-4 and IFN-γ levels after 5-AZA injection were evaluated. Plasma IL-4 and IL-4 expression in CD4  splenocytes declined with increasing age, while the IFN-γ expression levels increased. Th-related transcription factors showed no differences in mice at different weeks of age. The [[DNMT1]] and DNMT3b mRNA expression did not show significant changes in CD4  splenocytes, whereas the DNMT3a mRNA expression increased with age. DNA methylation in the IL-4 promoter was increased, while DNA methylation in the IFN-γ promoter was decreased. The methylation of RSH7, CNS-1, and HSV increased significantly with age. Age-related changes in DNA methylation may be associated with the shift in Th1/Th2 balance.
|mesh-terms=* Aging
* Animals
* Cytokines
* DNA Methylation
* Interferon-gamma
* Interleukin-4
* Mice
* Promoter Regions, Genetic
* Regulatory Sequences, Nucleic Acid
* Th1 Cells
* Th1-Th2 Balance
* Th2 Cells
|keywords=* T helper cell
* epigenetics
* methylation
|full-text-url=https://sci-hub.do/10.1007/s10753-016-0425-0
}}
{{medline-entry
|title=[[CDK4]]-[[CDK6]] inhibitors induce autophagy-mediated degradation of [[DNMT1]] and facilitate the senescence antitumor response.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/27532423
|abstract=Senescence is a natural anticancer defense program disabled in tumor cells. We discovered that deregulated [[CDK4]] (cyclin dependant kinase 4) and [[CDK6]] activities contribute to senescence bypass during tumorigenesis and that their inhibition restores the senescence response in tumor cells. [[CDK4]] and [[CDK6]] phosphorylate RB1/RB, preventing its inhibitory interaction with the E2Fs, the cell cycle transcription factors. However, we also found that [[CDK4]] interacts and phosphorylates the [[DNMT1]] (DNA methyltransferase 1) protein protecting it from macroautophagy/autophagy-mediated protein degradation. This discovery highlights a new epigenetic component of [[CDK4]]-[[CDK6]] signaling that could be exploited in cancer treatment.
|mesh-terms=* Autophagy
* Cellular Senescence
* Clinical Trials as Topic
* Cyclin-Dependent Kinase 4
* Cyclin-Dependent Kinase 6
* DNA (Cytosine-5-)-Methyltransferase 1
* DNA (Cytosine-5-)-Methyltransferases
* Humans
* Models, Biological
* Neoplasms
* Protein Kinase Inhibitors
* Proteolysis
|keywords=* CDK4
* DNMT1
* PML
* autophagy
* cancer
* epigenetic
* senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5079664
}}
{{medline-entry
|title=Developmental lead exposure and lifespan alterations in epigenetic regulators and their correspondence to biomarkers of Alzheimer's disease.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/27239543
|abstract=Early life lead (Pb) exposure results in a latent increase in Alzheimer's disease (AD)-related proteins, and cognitive deficits late in life in both rodents and primates. This study was conducted to investigate if these late life changes were accompanied by epigenetic alterations. Western blot analysis and RT-PCR were used to measure Deoxyribonucleic acid methylation regulators ([[DNMT1]], DNMT3a, MeCP2, MAT2A) and histone proteins (H3K9Ac, H3K4me2, H3K27me3). Cerebral levels of [[DNMT1]] and MeCP2 were significantly reduced in mice exposed to Pb early in life, whereas the expression of DNMT3a was not altered. Levels of MAT2a were increased in the Pb-exposed mice across the lifespan. H3K9Ac and H3K4me2, involved in gene activation, were decreased, whereas the repressive mark H3K27me3 was elevated. Epigenetic modifiers are affected by the developmental exposure to Pb and may play a role in mediating the latent increases in AD-related proteins in the brain.

|keywords=* Aging
* Alzheimer's disease
* Epigenetics
* Lead (Pb)
* Lifespan
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4879653
}}
{{medline-entry
|title=Age-dependent expression of [[DNMT1]] and [[DNMT3B]] in PBMCs from a large European population enrolled in the MARK-AGE study.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/27169697
|abstract=Aging is associated with alterations in the content and patterns of DNA methylation virtually throughout the entire human lifespan. Reasons for these variations are not well understood. However, several lines of evidence suggest that the epigenetic instability in aging may be traced back to the alteration of the expression of DNA methyltransferases. Here, the association of the expression of DNA methyltransferases [[DNMT1]] and [[DNMT3B]] with age has been analysed in the context of the MARK-AGE study, a large-scale cross-sectional study of the European general population. Using peripheral blood mononuclear cells, we assessed the variation of [[DNMT1]] and [[DNMT3B]] gene expression in more than two thousand age-stratified women and men (35-75 years) recruited across eight European countries. Significant age-related changes were detected for both transcripts. The level of [[DNMT1]] gradually dropped with aging but this was only observed up to the age of 64 years. By contrast, the expression of [[DNMT3B]] decreased linearly with increasing age and this association was particularly evident in females. We next attempted to trace the age-related changes of both transcripts to the influence of different variables that have an impact on changes of their expression in the population, including demographics, dietary and health habits, and clinical parameters. Our results indicate that age affects the expression of [[DNMT1]] and [[DNMT3B]] as an almost independent variable in respect of all other variables evaluated.
|mesh-terms=* Adult
* Aged
* Aging
* Body Mass Index
* DNA (Cytosine-5-)-Methyltransferase 1
* DNA (Cytosine-5-)-Methyltransferases
* European Continental Ancestry Group
* Female
* Gene Expression Regulation, Developmental
* Gene Expression Regulation, Enzymologic
* Gene Ontology
* Humans
* Leukocytes, Mononuclear
* Life Style
* Male
* Middle Aged
* RNA, Messenger
* Regression Analysis
* Risk Factors
|keywords=* DNA methylation
* DNMT1
* DNMT3B
* aging
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4933658
}}
{{medline-entry
|title=[[SIRT1]] affects DNA methylation of polycomb group protein target genes, a hotspot of the epigenetic shift observed in ageing.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/26104761
|abstract=[[SIRT1]] is likely to play a role in the extension in healthspan induced by dietary restriction. Actions of [[SIRT1]] are pleiotropic, and effects on healthspan may include effects on DNA methylation. Polycomb group protein target genes (PCGTs) are suppressed by epigenetic mechanisms in stem cells, partly through the actions of the polycomb repressive complexes (PRCs), and have been shown previously to correspond with loci particularly susceptible to age-related changes in DNA methylation. We hypothesised that [[SIRT1]] would affect DNA methylation particularly at PCGTs. To map the sites in the genome where [[SIRT1]] affects DNA methylation, we altered [[SIRT1]] expression in human intestinal (Caco-2) and vascular endothelial (HuVEC) cells by transient transfection with an expression construct or with siRNA. DNA was enriched for the methylated fraction then sequenced (HuVEC) or hybridised to a human promoter microarray (Caco-2). The profile of genes where [[SIRT1]] manipulation affected DNA methylation was enriched for PCGTs in both cell lines, thus supporting our hypothesis. [[SIRT1]] knockdown affected the mRNA for none of seven PRC components nor for [[DNMT1]] or DNMT3b. We thus find no evidence that [[SIRT1]] affects DNA methylation at PCGTs by affecting the expression of these gene transcripts. [[EZH2]], a component of PRC2 that can affect DNA methylation through association with DNA methyltransferases (DNMTs), did not co-immunoprecipitate with [[SIRT1]], and [[SIRT1]] knockdown did not affect the expression of [[EZH2]] protein. Thus, it is unlikely that the effects of [[SIRT1]] on DNA methylation at PCGTs are mediated through direct intermolecular association with [[EZH2]] or through effects in its expression. [[SIRT1]] affects DNA methylation across the genome, but particularly at PCGTs. Although the mechanism through which [[SIRT1]] has these effects is yet to be uncovered, this action is likely to contribute to extended healthspan, for example under conditions of dietary restriction.
|mesh-terms=* Aging
* Caco-2 Cells
* DNA (Cytosine-5-)-Methyltransferase 1
* DNA (Cytosine-5-)-Methyltransferases
* DNA Methylation
* DNA-Binding Proteins
* Enhancer of Zeste Homolog 2 Protein
* Epigenesis, Genetic
* Gene Expression Regulation
* Humans
* Polycomb Repressive Complex 2
* Polycomb-Group Proteins
* Promoter Regions, Genetic
* Sirtuin 1

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4480908
}}
{{medline-entry
|title=The Interplay Between miR-148a and [[DNMT1]] Might be Exploited for Pancreatic Cancer Therapy.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/25950085
|abstract=We discovered the expression level of miR-148a significantly decreased in pancreatic cancer tissues whereas that of [[DNMT1]] increased. In ASPC-1 cancer cells, the overexpression of miR-148a led to a decreased level of [[DNMT1]] and reduced the proliferation and metastasis of ASPC-1 cells. Moreover, the increased expression of miR-148a arrested the UTR methylation of p27, giving rise to an increased level of p27. Interestingly, it was shown that the [[DNMT1]] inhibition enhanced the expression of miR-148a. In vivo studies demonstrated that the tumorigenesis of ASPC-1 was significantly arrested by either the overexpression of miR-148a or the inhibition of [[DNMT1]]. 
|mesh-terms=* Animals
* Cell Line, Tumor
* Cyclin-Dependent Kinase Inhibitor p27
* DNA (Cytosine-5-)-Methyltransferase 1
* DNA (Cytosine-5-)-Methyltransferases
* DNA Methylation
* Gene Expression Regulation, Neoplastic
* Humans
* Mice
* MicroRNAs
* Molecular Targeted Therapy
* Neoplasm Metastasis
* Neoplasm Transplantation
* Pancreatic Neoplasms
* Untranslated Regions
|keywords=* DNMT1
* Pancreatic cancer
* Senescence
* miR-148a
* p27
|full-text-url=https://sci-hub.do/10.3109/07357907.2015.1025794
}}
{{medline-entry
|title=Expression of DNA methyltransferases is influenced by growth hormone in the long-living Ames dwarf mouse in vivo and in vitro.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/24201695
|abstract=Methyltransferase expression and DNA methylation are linked to aging and age-related disease. We utilized 3-, 12-, and 24-month-old Ames dwarf and their wild-type siblings to examine the genotype and age-related differences in the expression of methyltransferase enzymes related to DNA methylation in the liver, glycine-N-methyltransferase and DNA methyltransferase (DNMT). We found that DNMT proteins and transcripts are differentially expressed in dwarf mice compared with wild-type siblings that can be attributed to age and/or genotype. However, [[DNMT1]] protein expression is drastically reduced compared with wild-type controls at every age. DNMT3a protein levels coincide with differences observed in DNMT activity. Growth hormone appears to modulate expression of [[DNMT1]] and 3a in dwarf liver tissue and primary hepatocytes. Therefore, growth hormone may contribute to age-related processes, DNA methylation, and, ultimately, longevity. 
|mesh-terms=* Animals
* Colorimetry
* DNA (Cytosine-5-)-Methyltransferases
* DNA Methylation
* Dwarfism, Pituitary
* Glycine N-Methyltransferase
* Growth Hormone
* Hepatocytes
* Immunoblotting
* Longevity
* Methyltransferases
* Mice
* Mice, Inbred Strains
* Repressor Proteins
|keywords=* Aging
* Ames dwarf mice
* DNA methylation
* DNA methyltransferase
* Glycine-N-methyltransferase
* Liver.
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4111294
}}
{{medline-entry
|title=Exercise induces age-dependent changes on epigenetic parameters in rat hippocampus: a preliminary study.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/23201423
|abstract=Regular exercise improves learning and memory, including during aging process. Interestingly, the imbalance of epigenetic mechanisms has been linked to age-related cognitive deficits. However, studies about epigenetic alterations after exercise during the aging process are rare. In this preliminary study we investigated the effect of aging and exercise on DNA methyltransferases ([[DNMT1]] and DNMT3b) and H3-K9 methylation levels in hippocampus from 3 and 20-months aged Wistar rats. The animals were submitted to two exercise protocols: single session or chronic treadmill protocol. [[DNMT1]] and H3-K9 methylation levels were decreased in hippocampus from aged rats. The single exercise session decreased both DNMT3b and [[DNMT1]] levels in young adult rats, without any effect in the aged group. Both exercise protocols reduced H3-K9 methylation levels in young adult rats, while the single session reversed the changes on H3-K9 methylation levels induced by aging. Together, these results suggest that an imbalance on DNMTs and H3-K9 methylation levels might be linked to the brain aging process and that the outcome to exercise seems to vary through lifespan.
|mesh-terms=* Age Factors
* Aging
* Animals
* Biomarkers
* DNA (Cytosine-5-)-Methyltransferase 1
* DNA (Cytosine-5-)-Methyltransferases
* DNA Methylation
* Epigenesis, Genetic
* Hippocampus
* Histones
* Lysine
* Male
* Physical Exertion
* Rats
* Rats, Wistar

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4405233
}}
{{medline-entry
|title=The role of DNA methylation in aging, rejuvenation, and age-related disease.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/23098078
|abstract=DNA methylation is a major control program that modulates gene expression in a plethora of organisms. Gene silencing through methylation occurs through the activity of DNA methyltransferases, enzymes that transfer a methyl group from S-adenosyl-L-methionine to the carbon 5 position of cytosine. DNA methylation patterns are established by the de novo DNA methyltransferases (DNMTs) [[DNMT3A]] and [[DNMT3B]] and are subsequently maintained by [[DNMT1]]. Aging and age-related diseases include defined changes in 5-methylcytosine content and are generally characterized by genome-wide hypomethylation and promoter-specific hypermethylation. These changes in the epigenetic landscape represent potential disease biomarkers and are thought to contribute to age-related pathologies, such as cancer, osteoarthritis, and neurodegeneration. Some diseases, such as a hereditary form of sensory neuropathy accompanied by dementia, are directly caused by methylomic changes. Epigenetic modifications, however, are reversible and are therefore a prime target for therapeutic intervention. Numerous drugs that specifically target DNMTs are being tested in ongoing clinical trials for a variety of cancers, and data from finished trials demonstrate that some, such as 5-azacytidine, may even be superior to standard care. DNMTs, demethylases, and associated partners are dynamically shaping the methylome and demonstrate great promise with regard to rejuvenation.
|mesh-terms=* Aging
* Animals
* DNA Methylation
* DNA Modification Methylases
* Epigenesis, Genetic
* Humans
* Rejuvenation

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3482848
}}
{{medline-entry
|title=5-Lipoxygenase DNA methylation and mRNA content in the brain and heart of young and old mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/20052386
|abstract=The expression of 5-lipoxygenase (5-[[LOX]]) is affected by aging and regulated by epigenetic mechanisms including DNA methylation. We used methylation-sensitive restriction endonucleases (AciI, BstUI, HpaII, and HinP1I) to assess 5-[[LOX]] DNA methylation in brain and heart tissue samples from young (2 months) and old (22 months) mice. We also measured mRNA content for 5-[[LOX]] and the DNA methyltransferases [[DNMT1]] and DNMT3a. In young mice, the 5-[[LOX]] mRNA content was significantly greater in the heart compared to the brain; 5-[[LOX]] DNA methylation was lower, except in the AciI assay in which it was higher in the heart. Aging decreased 5-[[LOX]] mRNA content in the heart and increased it in the brain. Aging also increased 5-[[LOX]] DNA methylation and this effect was site- (i.e., enzyme) and tissue-specific. Generally, [[DNMT1]] and DNMT3a mRNA content was lower in the brain regions compared to the heart; the only effect of aging was observed in the mRNA content of DNMT3a, which was decreased in the heart of old mice. These results indicate a complex tissue-specific and aging-dependent interplay between the DNA methylation system and 5-[[LOX]] mRNA content. Interpretation of this data must take into account that the tissue samples contained a mixture of various cell types.
|mesh-terms=* Aging
* Animals
* Arachidonate 5-Lipoxygenase
* Brain
* DNA (Cytosine-5-)-Methyltransferase 1
* DNA (Cytosine-5-)-Methyltransferases
* DNA Methylation
* Down-Regulation
* Epigenesis, Genetic
* Gene Silencing
* Inflammation
* Leukotrienes
* Lipoxins
* Male
* Mice
* Mice, Inbred C57BL
* Myocardium
* Promoter Regions, Genetic
* RNA, Messenger
* Restriction Mapping

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2801004
}}
{{medline-entry
|title=Epigenetic regulation of estrogen receptor alpha gene expression in the mouse cortex during early postnatal development.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/19966177
|abstract=Estrogens play a critical role in brain development by acting on areas that express estrogen receptors. In the rodent cortex, estrogen receptor alpha (ER alpha) mRNA expression is high early in postnatal development but declines starting at postnatal day (PND) 10 and is virtually absent in the adult cortex. The mechanisms controlling this regulation are largely unknown. Methylation is important for gene silencing during development in many tissues, including the brain. In the present study, we examined the methylation status of ER alpha 5' untranslated exons during early postnatal development in male and female mice using methylation-specific PCR and pyrosequencing. Several regions of ER alpha promoter displayed a significant increase in methylation at PND 18 and 25 compared with PND 4. DNA methyltransferases (DNMT) are important for the initiation and maintenance of methylation. Real-time PCR showed that [[DNMT3A]], the de novo DNMT peaked at PND 10 and was decreased by PND 25. [[DNMT1]], which is important for maintenance of methylation, increased across development and stayed high in adult cortex. The methyl-CpG-binding protein 2 (MeCP2) is also important for stabilization of methylation. A chromatin immunoprecipitation assay showed a correlation between association of MeCP2 with ER alpha promoter and the increase in methylation and decrease in ER alpha expression after PND 10. In mice containing a mutant MeCP2 protein, ER alpha mRNA expression and promoter methylation patterns across development were different compared with wild-type mice. These data suggest that methylation of ER alpha promoters regulates ER alpha mRNA expression in the cortex during postnatal development in a MeCP2-dependent fashion.
|mesh-terms=* Aging
* Animals
* Cerebral Cortex
* DNA
* DNA (Cytosine-5-)-Methyltransferase 1
* DNA (Cytosine-5-)-Methyltransferases
* DNA Methylation
* DNA Primers
* Estrogen Receptor alpha
* Female
* Gene Expression Regulation, Developmental
* Male
* Methyl-CpG-Binding Protein 2
* Mice
* Mice, Inbred C57BL
* Polymerase Chain Reaction
* RNA, Messenger
* Sex Characteristics

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2817618
}}
{{medline-entry
|title=Epigenetic regulation of killer immunoglobulin-like receptor expression in T cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/19628706
|abstract=With increasing age, T cells gain expression of killer immunoglobulin-like receptors (KIRs) that transmit negative signals and dampen the immune response. KIR expression is induced in [[CD4]] and CD8 T cells by CpG DNA demethylation suggesting epigenetic control. To define the mechanisms that underlie the age-associated preferential KIR expression in CD8 T cells, we examined [[KIR2DL3]] promoter methylation patterns. With age, CD8 T cells developed a patchy and stochastic promoter demethylation even in cells that did not express the [[KIR2DL3]]-encoded CD158b protein; complete demethylation of the minimal [[KIR2DL3]] promoter was characteristic for CD158b-expressing cells. In contrast, the promoter in [[CD4]] T cells was fully methylated irrespective of age. The selectivity for CD8 T cells correlated with lower [[DNMT1]] recruitment to the [[KIR2DL3]] promoter which further diminished with age. In contrast, binding of the polycomb protein [[EZH2]] known to be involved in [[DNMT1]] recruitment was not different. Our data suggest that CD8 T cells endure increasing displacement of [[DNMT1]] from the KIR promoter with age, possibly because of an active histone signature. The ensuing partial demethylation lowers the threshold for transcriptional activation and renders CD8 T cells more susceptible to express KIR, thereby contributing to the immune defect in the elderly.
|mesh-terms=* Adult
* Aged
* Aged, 80 and over
* Aging
* CD4-Positive T-Lymphocytes
* CD8-Positive T-Lymphocytes
* CpG Islands
* DNA (Cytosine-5-)-Methyltransferase 1
* DNA (Cytosine-5-)-Methyltransferases
* DNA Methylation
* DNA-Binding Proteins
* Enhancer of Zeste Homolog 2 Protein
* Epigenesis, Genetic
* Female
* Humans
* Male
* Polycomb Repressive Complex 2
* Promoter Regions, Genetic
* Receptors, KIR2DL3
* Transcription Factors

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2765678
}}
{{medline-entry
|title=A method to detect DNA methyltransferase I gene transcription in vitro in aging systems.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/17634574
|abstract=Epigenetic alterations of DNA play key roles in determining gene structure and expression. Methylation of the 5-position of cytosine is thought to be the most common modification of the genome in mammals. Studies have generally shown that hypermethylation in gene regulatory regions is associated with inactivation and reduced transcription and that alteration in established methylation patterns during development can affect embryonic viability. Changes in methylation have also been associated with aging and cellular senescence as well as tumorogenesis. DNA methyltransferase 1 ([[DNMT1]]) is thought to play an important role in maintaining already established methylation patterns during DNA replication and catalyzes the transfer of a methyl moiety from S-adenosyl-L-methionine (SAM) to the 5-position of cytosines in the CpG dinucleotide. Several studies illustrate changes in activity and transcription of [[DNMT1]] during aging and here we show a comprehensive method of detection of [[DNMT1]] mRNA transcription from senescing cells in culture.
|mesh-terms=* Aging
* Animals
* Cell Culture Techniques
* Cell Transformation, Neoplastic
* Cells, Cultured
* Cellular Senescence
* DNA (Cytosine-5-)-Methyltransferase 1
* DNA (Cytosine-5-)-Methyltransferases
* DNA Methylation
* Epigenesis, Genetic
* Gene Expression Regulation
* Humans
* RNA, Messenger
* Transcription, Genetic
* Xenopus

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2423211
}}