A pharmacodynamic assay to monitor treatment with the hypomethylating cytosine analogs, decitabine and azacitidine.

Hypomethylating therapies using decitabine or azacitidine are actively investigated to treat acute myeloid leukemia, myelodysplastic syndromes, as maintenance therapy after allogenic stem cell transplant and hemoglobinopathies. The therapeutic mechanism is to de-repress genes that have been turned off through oncogenesis or development via methylation. The therapy can be non-cytotoxic at low dosage, sparing healthy stem cells and operating on committed precursors. Because the methods of determining maximum tolerated dose are not well suited to this paradigm, and because the mechanism of action, which is depletion of DNA methylase 1 (DNMT1), is complex and dependent on passing through a cell cycle, a pharmacodynamic assay that measures DNMT1 can inform clinical trials aimed at establishing and improving therapy. Herein, we provide an assay that measures DNMT1 relative levels in circulating T cells of peripheral blood.

Rhein suppresses esophageal cancer development by regulating cell cycle through DNMT3B gene.

The mechanism by which DNMT3B facilitates esophageal cancer (ESCA) progression is currently unknown, despite its association with adverse prognoses in several cancer types. To investigate the potential therapeutic effects of the Chinese herbal medicine rhubarb on esophageal cancer (ESCA), we adopted an integrated bioinformatics approach. Gene Set Enrichment Analysis (GSEA) was first utilized to screen active anti-ESCA components in rhubarb. We then employed Weighted Gene Co-expression Network Analysis (WGCNA) to identify key molecular modules and targets related to the active components and ESCA pathogenesis. This system-level strategy integrating multi-omics data provides a powerful means to unravel the molecular mechanisms underlying the anticancer activities of natural products, like rhubarb. To investigate module gene functional enrichment, Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted. In addition, we evaluated the predictive impact of DNMT3B expression on ESCA patients utilizing the Kaplan-Meier method. Finally, we conducted experiments on cell proliferation and the cell cycle to explore the biological roles of DNMT3B. In this study, we identified Rhein as the main active ingredient of rhubarb that exhibited significant anti-ESCA activity. Rhein markedly suppressed ESCA cell proliferation. Utilizing Weighted Gene Co-expression Network Analysis (WGCNA) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, we determined that the blue module was associated with Rhein target genes and the cell cycle. Additionally, DNMT3B was identified as a Rhein target gene. Analysis of The Cancer Genome Atlas (TCGA) database revealed that higher DNMT3B levels were associated with poor prognosis in ESCA patients. Furthermore, Rhein partially reversed the overexpression of DNMT3B to inhibit ESCA cell proliferation. In vitro studies demonstrated that Rhein and DNMT3B inhibition disrupted the S phase of the cell cycle and affected the production of cell cycle-related proteins. In this study, we found that Rhein exerts its anti-proliferative effects in ESCA cells by targeting DNMT3B and regulating the cell cycle.

Combined Effects of Clonal Hematopoiesis and Carotid Stenosis on Cardiovascular Mortality.

BACKGROUND: The expansion of hematopoietic stem cells caused by acquired somatic mutations (clonal hematopoiesis [CH]) is a novel cardiovascular risk factor. The prognostic value of CH in patients with carotid atherosclerosis remains to be evaluated. OBJECTIVES: This study assessed the prognostic significance of CH in patients with atherosclerosis as detected by ultrasound of the carotid artery. METHODS: We applied deep sequencing of selected genomic regions within the genes DNMT3A, TET2, ASXL1, and JAK2 to screen for CH in 968 prospectively collected patients with asymptomatic carotid atherosclerosis evaluated by duplex sonography. RESULTS: We detected clonal markers at variant allele frequency ≥2% in 133 (13.7%) of 968 patients (median age 69.2 years), with increasing prevalence at advanced age. Multivariate analyses including age and established cardiovascular risk factors revealed overall presence of CH to be significantly associated with increased risk of cardiovascular death (HR: 1.50; 95% CI: 1.12-2.00; P = 0.007), reflected also at the single gene level. The effect of CH was more pronounced in older patients and independent of the patients' inflammatory status as measured by high-sensitivity C-reactive protein. Simultaneous assessment of CH and degree of carotid stenosis revealed combined effects on cardiovascular mortality, depicted by a superior risk for patients with >50% stenosis and concomitant CH (adjusted HR: 1.60; 95% CI: 1.08-2.38; P = 0.020). CONCLUSIONS: CH status in combination with the extent of carotid atherosclerosis jointly predict long-term mortality. Determination of CH can provide additional prognostic information in patients with asymptomatic carotid atherosclerosis.

iChIP-SILAC analysis identifies epigenetic regulators of CpG methylation of the p16INK4A gene.

Allele-specific epigenetic events regulate the expression of specific genes such as tumor suppressor genes. Methods to biochemically identify epigenetic regulators remain limited. Here, we used insertional chromatin immunoprecipitation (iChIP) to address this issue. iChIP combined with quantitative mass spectrometry identified DNA methyltransferase 1 (DNMT1) and epigenetic regulators as proteins that potentially interact with a region of the p16INK4A gene that is CpG-methylated in one allele in HCT116 cells. Some of the identified proteins are involved in the CpG methylation of this region, and of these, DEAD-box helicase 24 (DDX24) contributes to CpG methylation by regulating the protein levels of DNMT1. Thus, iChIP is a useful method to identify proteins which bind to a target locus of interest.

Curcumin regulates pulmonary extracellular matrix remodeling and mitochondrial function to attenuate pulmonary fibrosis by regulating the miR-29a-3p/DNMT3A axis.

Epigenetic regulation and mitochondrial dysfunction are essential to the progression of idiopathic pulmonary fibrosis (IPF). Curcumin (CCM) in inhibits the progression of pulmonary fibrosis by regulating the expression of specific miRNAs and pulmonary fibroblast mitochondrial function; however, the underlying mechanism is unclear. C57BL/6 mice were intratracheally injected with bleomycin (5 mg/kg) and treated with CCM (25 mg/kg body weight/3 times per week, intraperitoneal injection) for 28 days. Verhoeff-Van Gieson, Picro sirius red, and Masson's trichrome staining were used to examine the expression and distribution of collagen and elastic fibers in the lung tissue. Pulmonary fibrosis was determined using micro-computed tomography and transmission electron microscopy. Human pulmonary fibroblasts were transfected with miR-29a-3p, and RT-qPCR, immunostaining, and western blotting were performed to determine the expression of DNMT3A and extracellular matrix collagen-1 (COL1A1) and fibronectin-1 (FN1) levels. The expression of mitochondrial electron transport chain complex (MRC) and mitochondrial function were detected using western blotting and Seahorse XFp Technology. CCM in increased the expression of miR-29a-3p in the lung tissue and inhibited the DNMT3A to reduce the COL1A1 and FN1 levels leading to pulmonary extracellular matrix remodeling. In addition, CCM inhibited pulmonary fibroblasts MRC and mitochondrial function via the miR-29a-3p/DNMT3A pathway. CCM attenuates pulmonary fibrosis via the miR-29a-3p/DNMT3A axis to regulate extracellular matrix remodeling and mitochondrial function and may provide a new therapeutic intervention for preventing pulmonary fibrosis.

Downregulation of UBB potentiates SP1/VEGFA-dependent angiogenesis in clear cell renal cell carcinoma.

Clear cell renal cell carcinoma (ccRCC) presents a unique profile characterized by high levels of angiogenesis and robust vascularization. Understanding the underlying mechanisms driving this heterogeneity is essential for developing effective therapeutic strategies. This study revealed that ubiquitin B (UBB) is downregulated in ccRCC, which adversely affects the survival of ccRCC patients. UBB exerts regulatory control over vascular endothelial growth factor A (VEGFA) by directly interacting with specificity protein 1 (SP1), consequently exerting significant influence on angiogenic processes. Subsequently, we validated that DNA methyltransferase 3 alpha (DNMT3A) is located in the promoter of UBB to epigenetically inhibit UBB transcription. Additionally, we found that an unharmonious UBB/VEGFA ratio mediates pazopanib resistance in ccRCC. These findings underscore the critical involvement of UBB in antiangiogenic therapy and unveil a novel therapeutic strategy for ccRCC.

Natural history of clonal haematopoiesis seen in real-world haematology settings.

Recursive partitioning of healthy consortia led to the development of the Clonal Hematopoiesis Risk Score (CHRS) for clonal haematopoiesis (CH); however, in the practical setting, most cases of CH are diagnosed after patients present with cytopenias or related symptoms. To address this real-world population, we characterize the clinical trajectories of 94 patients with CH and distinguish CH harbouring canonical DNMT3A/TET2/ASXL1 mutations alone ('sole DTA') versus all other groups ('non-sole DTA'). TET2, rather than DNMT3A, was the most prevalent mutation in the real-world setting. Sole DTA patients did not progress to myeloid neoplasm (MN) in the absence of acquisition of other mutations. Contrastingly, 14 (20.1%) of 67 non-sole DTA patients progressed to MN. CHRS assessment showed a higher frequency of high-risk CH in non-sole DTA (vs. sole DTA) patients and in progressors (vs. non-progressors). RUNX1 mutation conferred the strongest risk for progression to MN (odds ratio [OR] 10.27, 95% CI 2.00-52.69, p = 0.0053). The mean variant allele frequency across all genes was higher in progressors than in non-progressors (36.9% ± 4.62% vs. 24.1% ± 1.67%, p = 0.0064). This analysis in the post-CHRS era underscores the natural history of CH, providing insight into patterns of progression to MN.

Natural bioactive compounds targeting DNA methyltransferase enzymes in cancer: Mechanisms insights and efficiencies.

The regulation of gene expression is fundamental to health and life and is essentially carried out at the promoter region of the DNA of each gene. Depending on the molecular context, this region may be accessible or non-accessible (possibility of integration of RNA polymerase or not at this region). Among enzymes that control this process, DNA methyltransferase enzymes (DNMTs), are responsible for DNA demethylation at the CpG islands, particularly at the promoter regions, to regulate transcription. The aberrant activity of these enzymes, i.e. their abnormal expression or activity, can result in the repression or overactivation of gene expression. Consequently, this can generate cellular dysregulation leading to instability and tumor development. Several reports highlighted the involvement of DNMTs in human cancers. The inhibition or activation of DNMTs is a promising therapeutic approach in many human cancers. In the present work, we provide a comprehensive and critical summary of natural bioactive molecules as primary inhibitors of DNMTs in human cancers. The active compounds hold the potential to be developed as anti-cancer epidrugs targeting DNMTs.

DNMT3A Cooperates with YAP/TAZ to Drive Gallbladder Cancer Metastasis.

Gallbladder cancer (GBC) is an extremely lethal malignancy with aggressive behaviors, including liver or distant metastasis; however, the underlying mechanisms driving the metastasis of GBC remain poorly understood. In this study, it is found that DNA methyltransferase DNMT3A is highly expressed in GBC tumor tissues compared to matched adjacent normal tissues. Clinicopathological analysis shows that DNMT3A is positively correlated with liver metastasis and poor overall survival outcomes in patients with GBC. Functional analysis confirms that DNMT3A promotes the metastasis of GBC cells in a manner dependent on its DNA methyltransferase activity. Mechanistically, DNMT3A interacts with and is recruited by YAP/TAZ to recognize and access the CpG island within the CDH1 promoter and generates hypermethylation of the CDH1 promoter, which leads to transcriptional silencing of CDH1 and accelerated epithelial-to-mesenchymal transition. Using tissue microarrays, the association between the expression of DNMT3A, YAP/TAZ, and CDH1 is confirmed, which affects the metastatic ability of GBC. These results reveal a novel mechanism through which DNMT3A recruitment by YAP/TAZ guides DNA methylation to drive GBC metastasis and provide insights into the treatment of GBC metastasis by targeting the functional connection between DNMT3A and YAP/TAZ.

DNMT3L inhibits hepatocellular carcinoma progression through DNA methylation of CDO1: insights from big data to basic research.

BACKGROUND: DNMT3L is a crucial DNA methylation regulatory factor, yet its function and mechanism in hepatocellular carcinoma (HCC) remain poorly understood. Bioinformatics-based big data analysis has increasingly gained significance in cancer research. Therefore, this study aims to elucidate the role of DNMT3L in HCC by integrating big data analysis with experimental validation. METHODS: Dozens of HCC datasets were collected to analyze the expression of DNMT3L and its relationship with prognostic indicators, and were used for molecular regulatory relationship evaluation. The effects of DNMT3L on the malignant phenotypes of hepatoma cells were confirmed in vitro and in vivo. The regulatory mechanisms of DNMT3L were explored through MSP, western blot, and dual-luciferase assays. RESULTS: DNMT3L was found to be downregulated in HCC tissues and associated with better prognosis. Overexpression of DNMT3L inhibits cell proliferation and metastasis. Additionally, CDO1 was identified as a target gene of DNMT3L and also exhibits anti-cancer effects. DNMT3L upregulates CDO1 expression by competitively inhibiting DNMT3A-mediated methylation of CDO1 promoter. CONCLUSIONS: Our study revealed the role and epi-transcriptomic regulatory mechanism of DNMT3L in HCC, and underscored the essential role and applicability of big data analysis in elucidating complex biological processes.

Rapid and accurate remethylation of DNA in Dnmt3a-deficient hematopoietic cells with restoration of DNMT3A activity.

Here, we characterize the DNA methylation phenotypes of bone marrow cells from mice with hematopoietic deficiency of Dnmt3a or Dnmt3b (or both enzymes) or expressing the dominant-negative Dnmt3aR878H mutation [R882H in humans; the most common DNMT3A mutation found in acute myeloid leukemia (AML)]. Using these cells as substrates, we defined DNA remethylation after overexpressing wild-type (WT) DNMT3A1, DNMT3B1, DNMT3B3 (an inactive splice isoform of DNMT3B), or DNMT3L (a catalytically inactive "chaperone" for DNMT3A and DNMT3B in early embryogenesis). Overexpression of DNMT3A for 2 weeks reverses the hypomethylation phenotype of Dnmt3a-deficient cells or cells expressing the R878H mutation. Overexpression of DNMT3L (which is minimally expressed in AML cells) also corrects the hypomethylation phenotype of Dnmt3aR878H/+ marrow, probably by augmenting the activity of WT DNMT3A encoded by the residual WT allele. DNMT3L reactivation may represent a previously unidentified approach for restoring DNMT3A activity in hematopoietic cells with reduced DNMT3A function.

DNMT3B PWWP mutations cause hypermethylation of heterochromatin.

The correct establishment of DNA methylation patterns is vital for mammalian development and is achieved by the de novo DNA methyltransferases DNMT3A and DNMT3B. DNMT3B localises to H3K36me3 at actively transcribing gene bodies via its PWWP domain. It also functions at heterochromatin through an unknown recruitment mechanism. Here, we find that knockout of DNMT3B causes loss of methylation predominantly at H3K9me3-marked heterochromatin and that DNMT3B PWWP domain mutations or deletion result in striking increases of methylation in H3K9me3-marked heterochromatin. Removal of the N-terminal region of DNMT3B affects its ability to methylate H3K9me3-marked regions. This region of DNMT3B directly interacts with HP1α and facilitates the bridging of DNMT3B with H3K9me3-marked nucleosomes in vitro. Our results suggest that DNMT3B is recruited to H3K9me3-marked heterochromatin in a PWWP-independent manner that is facilitated by the protein's N-terminal region through an interaction with a key heterochromatin protein. More generally, we suggest that DNMT3B plays a role in DNA methylation homeostasis at heterochromatin, a process which is disrupted in cancer, aging and Immunodeficiency, Centromeric Instability and Facial Anomalies (ICF) syndrome.

The interaction of RELN-DNMT genes involving in neurotrophin signaling pathway contributes to schizophrenia susceptibility.

OBJECTIVE: Schizophrenia belongs to a severe mental illness with complicated clinical presentations, an ill-defined pathogenesis, and no known cause. Many genetic studies imply that polygenic interaction is important in the development of schizophrenia. The main mechanism of the RELN-BDNF-CREB-DNMT signaling pathway in neurodevelopment involves RELN, brain-derived neurotrophic factor (BDNF), transcription factor cyclic adenosine monophosphate response element binding protein (CREB), DNA methyltransferase 1 (DNMT1), as well as DNA methyltransferase 3B (DNMT3B). An early case-control research on 15 polymorphisms in the RELN, CREB, BDNF, DNMT1, and DNMT3B genes was done. A single gene variation has little effect on the pathogenesis of schizophrenia, but the combination of intergenic variation loci has a bigger impact because schizophrenia is a complex polygenic disorder. The objective of the current study sought to explore the impact of genetic interactions between RELN, BDNF, CREB, DNMT1, and DNMT3B on schizophrenia in order to further highlight the genetic factors influencing the risk of schizophrenia. METHODS: Taking the case-control study design, with the Diagnostic and Statistical Manual of Mental Disorders-Fifth Edition (DSM-5) to be the evaluation norm, 134 individuals suffering from schizophrenia hospitalized in the Third People's Hospital of Zhongshan City within January 2018 to April 2020 (case group) were selected, and 64 healthy individuals (control group) from the same geographical area had been chosen as well. MassArray identified DNMT1 gene single nucleotide polymorphisms (rs2114724 and rs2228611) and DNMT3B gene SNPs (rs2424932, rs1569686, rs6119954, and rs2424908). Using the generalized multifactor dimensionality reduction (GMDR), the RELN-BDNF-CREB-DNMT pathway's gene interactions were examined for their impact on schizophrenia. RESULTS: GMDR analysis showed that the three-order interaction model RELN (rs2073559, rs2229864)-DNMT3B (rs2424908) was the optimal model (p = 0.001), with the consistency of cross-validation of 10/10 and the test accuracy of 0.8711. CONCLUSION: The interaction between the RELN (rs2073559, rs2229864)-DNMT3B (rs2424908) may be related to schizophrenia, and large sample sizes should be verified in different population.

DNMT1/DNMT3a-mediated promoter hypermethylation and transcription activation of ICAM5 augments thyroid carcinoma progression.

Promoter methylation is one of the most studied epigenetic modifications and it is highly relevant to the onset and progression of thyroid carcinoma (THCA). This study investigates the promoter methylation and expression pattern of intercellular adhesion molecule 5 (ICAM5) in THCA. CpG islands with aberrant methylation pattern in THCA, and the expression profiles of the corresponding genes in THCA, were analyzed using bioinformatics. ICAM5 was suggested to have a hypermethylation status, and it was highly expressed in THCA tissues and cells. Its overexpression promoted proliferation, mobility, and tumorigenic activity of THCA cells. As for the downstream signaling, ICAM5 was found to activate the MAPK/ERK and MAPK/JNK signaling pathways. Either inhibition of ERK or JNK blocked the oncogenic effects of ICAM5. DNA methyltransferases 1 (DNMT1) and DNMT3a were found to induce promoter hypermethylation of ICAM5 in THCA cells. Knockdown of DNMT1 or DNMT3a decreased the ICAM5 expression and suppressed malignant properties of THCA cells in vitro and in vivo, which were, however, restored by further artificial ICAM5 overexpression. Collectively, this study reveals that DNMT1 and DNMT3a mediates promoter hypermethylation and transcription activation of ICAM5 in THCA, which promotes malignant progression of THCA through the MAPK signaling pathway.

DNMT3A clonal hematopoiesis-driver mutations induce cardiac fibrosis by paracrine activation of fibroblasts.

Hematopoietic mutations in epigenetic regulators like DNA methyltransferase 3 alpha (DNMT3A), play a pivotal role in driving clonal hematopoiesis of indeterminate potential (CHIP), and are associated with unfavorable outcomes in patients suffering from heart failure (HF). However, the precise interactions between CHIP-mutated cells and other cardiac cell types remain unknown. Here, we identify fibroblasts as potential partners in interactions with CHIP-mutated monocytes. We used combined transcriptomic data derived from peripheral blood mononuclear cells of HF patients, both with and without CHIP, and cardiac tissue. We demonstrate that inactivation of DNMT3A in macrophages intensifies interactions with cardiac fibroblasts and increases cardiac fibrosis. DNMT3A inactivation amplifies the release of heparin-binding epidermal growth factor-like growth factor, thereby facilitating activation of cardiac fibroblasts. These findings identify a potential pathway of DNMT3A CHIP-driver mutations to the initiation and progression of HF and may also provide a compelling basis for the development of innovative anti-fibrotic strategies.

A review on recent advances in assays for DNMT1: a promising diagnostic biomarker for multiple human cancers.

The abnormal expression of human DNA methyltransferases (DNMTs) is closely related with the occurrence and development of a wide range of human cancers. DNA (cytosine-5)-methyltransferase-1 (DNMT1) is the most abundant human DNA methyltransferase and is mainly responsible for genomic DNA methylation patterns. Abnormal expression of DNMT1 has been found in many kinds of tumors, and DNMT1 has become a valuable target for the diagnosis and drug therapy of diseases. Nowadays, DNMT1 has been found to be involved in multiple cancers such as pancreatic cancer, breast cancer, bladder cancer, lung cancer, gastric cancer and other cancers. In order to achieve early diagnosis and for scientific research, various analytical methods have been developed for qualitative or quantitative detection of low-abundance DNMT1 in biological samples and human tumor cells. Herein, we provide a brief explication of the research progress of DNMT1 involved in various cancer types. In addition, this review focuses on the types, principles, and applications of DNMT1 detection methods, and discusses the challenges and potential future directions of DNMT1 detection.

Suppression of DNMT2/3 by proinflammatory cytokines inhibits CtBP1/2-dependent genes to promote the occurrence of atrophic nonunion.

Failure of bone healing after fracture often results in nonunion, but the underlying mechanism of nonunion pathogenesis is poorly understood. Herein, we provide evidence to clarify that the inflammatory microenvironment of atrophic nonunion (AN) mice suppresses the expression levels of DNA methyltransferases 2 (DNMT2) and 3A (DNMT3a), preventing the methylation of CpG islands on the promoters of C-terminal binding protein 1/2 (CtBP1/2) and resulting in their overexpression. Increased CtBP1/2 acts as transcriptional corepressors that, along with histone acetyltransferase p300 and Runt-related transcription factor 2 (Runx2), suppress the expression levels of six genes involved in bone healing: BGLAP (bone gamma-carboxyglutamate protein), ALPL (alkaline phosphatase), SPP1 (secreted phosphoprotein 1), COL1A1 (collagen 1a1), IBSP (integrin binding sialoprotein), and MMP13 (matrix metallopeptidase 13). We also observe a similar phenomenon in osteoblast cells treated with proinflammatory cytokines or treated with a DNMT inhibitor (5-azacytidine). Forced expression of DNMT2/3a or blockage of CtBP1/2 with their inhibitors can reverse the expression levels of BGLAP/ALPL/SPP1/COL1A1/IBSP/MMP13 in the presence of proinflammatory cytokines. Administration of CtBP1/2 inhibitors in fractured mice can prevent the incidence of AN. Thus, we demonstrate that the downregulation of bone healing genes dependent on proinflammatory cytokines/DNMT2/3a/CtBP1/2-p300-Runx2 axis signaling plays a critical role in the pathogenesis of AN. Disruption of this signaling may represent a new therapeutic strategy to prevent AN incidence after bone fracture.

Ectoine Globally Hypomethylates DNA in Skin Cells and Suppresses Cancer Proliferation.

Epigenetic modifications, mainly aberrant DNA methylation, have been shown to silence the expression of genes involved in epigenetic diseases, including cancer suppression genes. Almost all conventional cancer therapeutic agents, such as the DNA hypomethylation drug 5-aza-2-deoxycytidine, have insurmountable side effects. To investigate the role of the well-known DNA protectant (ectoine) in skin cell DNA methylation and cancer cell proliferation, comprehensive methylome sequence analysis, 5-methyl cytosine (5mC) analysis, proliferation and tumorigenicity assays, and DNA epigenetic modifications-related gene analysis were performed. The results showed that extended ectoine treatment globally hypomethylated DNA in skin cells, especially in the CpG island (CGIs) element, and 5mC percentage was significantly reduced. Moreover, ectoine mildly inhibited skin cell proliferation and did not induce tumorigenicity in HaCaT cells injected into athymic nude mice. HaCaT cells treated with ectoine for 24 weeks modulated the mRNA expression levels of Dnmt1, Dnmt3a, Dnmt3b, Dnmt3l, Hdac1, Hdac2, Kdm3a, Mettl3, Mettl14, Snrpn, and Mest. Overall, ectoine mildly demethylates DNA in skin cells, modulates the expression of epigenetic modification-related genes, and reduces cell proliferation. This evidence suggests that ectoine is a potential anti-aging agent that prevents DNA hypermethylation and subsequently activates cancer-suppressing genes.

The Role of Clonal Hematopoiesis of Indeterminant Potential and DNA (Cytosine-5)-Methyltransferase Dysregulation in Pulmonary Arterial Hypertension and Other Cardiovascular Diseases.

DNA methylation is an epigenetic mechanism that regulates gene expression without altering gene sequences in health and disease. DNA methyltransferases (DNMTs) are enzymes responsible for DNA methylation, and their dysregulation is both a pathogenic mechanism of disease and a therapeutic target. DNMTs change gene expression by methylating CpG islands within exonic and intergenic DNA regions, which typically reduces gene transcription. Initially, mutations in the DNMT genes and pathologic DNMT protein expression were found to cause hematologic diseases, like myeloproliferative disease and acute myeloid leukemia, but recently they have been shown to promote cardiovascular diseases, including coronary artery disease and pulmonary hypertension. We reviewed the regulation and functions of DNMTs, with an emphasis on somatic mutations in DNMT3A, a common cause of clonal hematopoiesis of indeterminant potential (CHIP) that may also be involved in the development of pulmonary arterial hypertension (PAH). Accumulation of somatic mutations in DNMT3A and other CHIP genes in hematopoietic cells and cardiovascular tissues creates an inflammatory environment that promotes cardiopulmonary diseases, even in the absence of hematologic disease. This review summarized the current understanding of the roles of DNMTs in maintenance and de novo methylation that contribute to the pathogenesis of cardiovascular diseases, including PAH.

An updated meta-analysis investigating the association between DNMTs gene polymorphism andgastric cancer risk.

Gastric cancer (GC) is a prominent global health issue, as it ranks as the fifth most prevalent type of cancer and the fourth most significant cause of cancer-related mortality worldwide. Although H. pylori is known to play a role in the development of GC, genetic factors also play a role in its onset and progression. Recent studies have shown that genetic polymorphisms are strongly associated with the development of GC and that certain single nucleotide polymorphisms (SNPs) can be used as biomarkers for early diagnosis and prevention. Epigenetic disturbances, such as DNA methylation, are involved in the development of GC, and mutations in the DNA methyltransferase (DNMT) gene have been found to increase the risk of GC. However, previous findings on the association between DNMTs SNPs and GC risk have been inconsistent. In this study, an updated meta-analysis of three well-studied and controversial DNMTs polymorphic loci, DNMT1 rs16999593, DNMT3A rs1550117 and DNMT3B rs1569686, was performed to provide more reliable results. It was found that DNMT1 rs16999593 was not associated with GC, DNMT3A rs1550117 may have a positive association with GC risk, and DNMT3B rs1569686 may be a protective factor for GC. These findings may provide valuable information for early diagnosis and prevention of GC, but further studies are needed to confirm these results.