[Detection ofmethylated genes related to allergic rhinitis and establishment of methylation profile].
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Objective:The aim of this study is to detect differentially methylated genes to allergic rhinitis (AR) based on methylation chip, and to analyze the relationship between DNA methylation and AR.Method:Illumina methylation chip were made by normal inferior turbinate mucous tissue obtained from patients(n=19) and healthy individuals(n=11). Detection of differential the sites of methylated genes, Gene Ontology enrichment, KEGG pathway enrichment database and literature search were used to analysis.Result:There were 94 aberrant methylation sites in patients with AR, including 51 hypermethylation sites (e.g. ST7,LCE2D,ATRIP genes) and 43 hypomethylation sites (e.g. PIK3CG, TLR6, IL-4 genes). The results of Gene Ontology enrichment and KEGG pathway enrichment indicates the DNA methylation has relative trend with AR, and DNA methylation of ST7, LCE2D, PIK3CG genes may be associated with AR, but the results of GO analysis and KEGG analysis were statistically significant. Moreover, literature search prompts that DNA methylation of TLR6 gene and IL-4 gene may be associated with AR.Conclusion:Varying degrees of methylated genes from inferior turbinate mucous tissue based on high-flux methylation chip hint gene methylation is an important cause of AR. The relationship between them needs further verification.Keywords:
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The aim of the study was to conduct a functional analysis of sex-specific age-related changes in DNA methylation.Materials and Methods.The study used a GSE87571 methylation dataset obtained from the blood DNA of 729 individuals aged 14 to 94 using the Illumina Infinium HumanMethylation450K BeadChip (USA).Gene ontology analysis was performed for 3 groups of genes (females, males, and duplicates) using the PANTHER database.The DAVID platform was used to perform KEGG metabolic pathway analysis.Results.The studies revealed unique for males and females changes in methylation of CpG sites, associated with certain metabolic processes.It was demonstrated that most of the CpG sites, for which methylation changes with age were revealed in both sexes, are associated with the genes responsible for the development and functioning of the nervous system.In males, unique age-related methylation changes affect CpG sites associated with changes in the immune system and lipid metabolism.In females, most CpGs are associated with changes involved in transcription and translation processes.Analysis of biological functions by KEGG revealed that a unique process associated with age-related changes in methylation of the glutamatergic system is typical for males.In females, unique biological processes with age-related changes include genes responsible for the development of diabetes and genes associated with cAMP signaling cascades (KEGG:04024). Conclusion.Our studies reveal fundamental features of sex-dependent changes in methylation of CpG sites with variance increasing, which may indicate differences in age-related changes.
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Differentially methylated regions
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Acute coronary syndrome (ACS) is a common disease with high mortality and morbidity rates. The methylation status of blood DNA may serve as a potential early diagnosis and prevention biomarker for numerous diseases. The present study was designed to explore novel genome-wide aberrant DNA methylation patterns associated with ACS. The Infinium HumanMethylation450 assay was used to examine genome-wide DNA methylation profiles in 3 pairs of ACS and control group samples. Epigenome-wide DNA methylation, genomic distribution, Gene Ontology (GO) term and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed. The results were confirmed using methylation-specific polymerase chain reaction (MSP) and Sequenom MassARRAY analyses in ACS, stable coronary artery disease (SCAD) and control samples. A total of 11,342 differentially methylated (DM) 5'-C-phosphate-G-3' (CpG) sites were identified, including 8,865 hypomethylated and 2,477 hypermethylated CpG sites in the ACS group compared with the control samples. They varied in frequency across genomic compartments, but were particularly notable in gene bodies and shores. The results of GO term and KEGG pathway enrichment analyses revealed that the methylated genes were associated with certain biological processes and pathways. Despite the considerable variability in methylation data, the candidate selected possessed significant methylation alteration in mothers against decapentaplegic homolog 3 (SMAD3) transcription start site 155 (Chr1:67356838-Chr1:67356942). MSP analysis from 81 ACS samples, 74 SCAD samples and 53 healthy samples, and Sequenom MassARRAY analysis, confirmed that differential CpG methylation of SMAD3 was significantly corrected with the reference results of the HumanMethylation450 array. The data identified an ACS-specific DNA methylation profile with a large number of novel DM CpG sites, some of which may serve as candidate markers for the early diagnosis of ACS.
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Objective:The aim of this study is to detect differentially methylated genes to allergic rhinitis (AR) based on methylation chip, and to analyze the relationship between DNA methylation and AR.Method:Illumina methylation chip were made by normal inferior turbinate mucous tissue obtained from patients(n=19) and healthy individuals(n=11). Detection of differential the sites of methylated genes, Gene Ontology enrichment, KEGG pathway enrichment database and literature search were used to analysis.Result:There were 94 aberrant methylation sites in patients with AR, including 51 hypermethylation sites (e.g. ST7,LCE2D,ATRIP genes) and 43 hypomethylation sites (e.g. PIK3CG, TLR6, IL-4 genes). The results of Gene Ontology enrichment and KEGG pathway enrichment indicates the DNA methylation has relative trend with AR, and DNA methylation of ST7, LCE2D, PIK3CG genes may be associated with AR, but the results of GO analysis and KEGG analysis were statistically significant. Moreover, literature search prompts that DNA methylation of TLR6 gene and IL-4 gene may be associated with AR.Conclusion:Varying degrees of methylated genes from inferior turbinate mucous tissue based on high-flux methylation chip hint gene methylation is an important cause of AR. The relationship between them needs further verification.
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DNA methylation is a part of epigenetic modification, that is closely related to the growth and development of colorectal cancer (CRC). Specific methylated genes and methylated diagnostic models of tumors have become current research focuses. The methylation status of circulating DNA in plasma might serve as a potential biomarker for CRC.To investigate genome-wide methylation pattern in early CRC using the Illumina Infinium Human Methylation 850K BeadChip.The 850K Methylation BeadChip was used to analyze the genome-wide methylation status of early CRC patients (n = 5) and colorectal adenoma patients (n = 5). Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways enrichment analyses were performed on the selected differentially methylated sites to further discover candidate methylation biomarkers in plasma.A total of 1865 methylated CpG sites with significant differences were detected, including 676 hypermethylated sites and 1189 hypomethylated sites. The distribution of these sites covered from the 1st to 22nd chromosomes and are mainly distributed on the gene body and gene promoter region. GO and KEGG enrichment analysis showed that the functions of these genes were related to biological regulation, molecular binding, transcription factor activity and signal transduction pathway.The study demonstrated that the Illumina Infinium Human Methylation 850K BeadChip can be used to investigate genome-wide methylation status of plasma DNA in early CRC and colorectal adenoma patients.
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A Genome-Wide Methylation Approach Identifies a New Hypermethylated Gene Panel in Ulcerative Colitis
The cause of inflammatory bowel disease (IBD) is still unknown, but there is growing evidence that environmental factors such as epigenetic changes can contribute to the disease etiology. The aim of this study was to identify newly hypermethylated genes in ulcerative colitis (UC) using a genome-wide DNA methylation approach. Using an Infinium HumanMethylation450 BeadChip array, we screened the DNA methylation changes in three normal colon controls and eight UC patients. Using these methylation profiles, 48 probes associated with CpG promoter methylation showed differential hypermethylation between UC patients and normal controls. Technical validations for methylation analyses in a larger series of UC patients (n = 79) were performed by methylation-specific PCR (MSP) and bisulfite sequencing analysis. We finally found that three genes (FAM217B, KIAA1614 and RIBC2) that were significantly elevating the promoter methylation levels in UC compared to normal controls. Interestingly, we confirmed that three genes were transcriptionally silenced in UC patient samples by qRT-PCR, suggesting that their silencing is correlated with the promoter hypermethylation. Pathway analyses were performed using GO and KEGG databases with differentially hypermethylated genes in UC. Our results highlight that aberrant hypermethylation was identified in UC patients which can be a potential biomarker for detecting UC. Moreover, pathway-enriched hypermethylated genes are possibly implicating important cellular function in the pathogenesis of UC. Overall, this study describes a newly hypermethylated gene panel in UC patients and provides new clinical information that can be used for the diagnosis and therapeutic treatment of IBD.
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Abstract BACKGROUND We previously demonstrated that a putative anti‐tumor gene, peroxisomal membrane protein 4, 24 kDa ( PMP24 or PXMP4 ), is silenced via DNA methylation of a CpG island in its 5′ flanking region (5′‐CGI) in prostate cancer (PCa) cells. METHODS To identify demethylation hypersensitive site(s) in PMP24 5′‐CGI, PC‐3 cells with methylated 5′‐CGI were treated with a low‐dose of 5‐aza‐2′‐deoxycytidine (5‐aza‐dC) just sufficient to reactivate gene expression, referred as the limited demethylation approach . Gel shift assays and promoter analyzes were performed to demonstrate the role of the hypersensitive site in PMP24 gene regulation. Transfection of a methylated oligonucleotide corresponding to the hypersensitive site was conducted to determine the effect of site‐specific methylation on the gene expression. Bisulfite sequencing analysis was performed to reveal the methylation status of PMP24 promoter in cultured cells and microdissected samples. In situ hybridization was applied to determine expression positivity of PMP24 mRNA. RESULTS A 5‐aza‐dC hypersensitive site encompasses two CpG dinucleotides in intron 1 was identified. Methylation of the first, but not the second, CpG dinucleotide of this site disrupted DNA–protein interactions and suppressed the gene expression. Using archival specimens, we found the first CpG dinucleotide of the hypersensitive site is hypermethylated with a loss of PMP24 mRNA expression in microdissected PCa cells when compared to normal prostatic epithelial cells. CONCLUSIONS These findings support a critical role for a single intronic CpG dinucleotide in PMP24 gene regulation through DNA methylation. The data suggest that methylation‐mediated silencing of PMP24 is a molecular event associated with prostate carcinogenesis. Prostate 70: 765–776, 2010. © 2010 Wiley‐Liss, Inc.
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Although there is growing evidence that exposure to ambient particulate matter is associated with global DNA methylation and gene-specific methylation, little is known regarding epigenome-wide changes in DNA methylation in relation to particles and, especially, particle components. Using the Illumina Infinium HumanMethylation450 BeadChip, we examined the relationship between one-year moving averages of PM2.5 species (Al, Ca, Cu, Fe, K, Na, Ni, S, Si, V, and Zn) and DNA methylation at 484,613 CpG probes in a longitudinal cohort that included 646 subjects. Bonferroni correction was applied to adjust for multiple comparisons. Bioinformatics analysis of the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment was also performed. We observed 20 Bonferroni significant (P-value < 9.4× 10−9) CpGs for Fe, 8 for Ni, and 1 for V. Particularly, methylation at Schlafen Family Member 11 (SLFN11) cg10911913 was positively associated with measured levels of all 3 species. The SLFN11 gene codes for an interferon-induced protein that inhibits retroviruses and sensitizes cancer cells to DNA-damaging agents. Bioinformatics analysis suggests that gene targets may be relevant to pathways including cancers, signal transduction, and cell growth and death. Ours is the first study to examine the epigenome-wide association between ambient particles species and DNA methylation. We found that long-term exposures to specific components of ambient particle pollution, especially particles emitted during oil combustion, were associated with methylation changes in genes relevant to immune responses. Our findings provide insight into potential biologic mechanisms on an epigenetic level.
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Objective: This study aims to characterize the abnormal changes in placental DNA methylation associated with conotruncal heart defects (CTDs) and the level of methylation as epigenetic biomarkers for CTDs detection. Methods: This was a prospective study involving 28 fetuses diagnosed with CTDs in the second trimester at Beijing Anzhen Hospital between September 2020 and June 2021. These cases were classified into four groups based on their subtypes. 12 normal fetuses were used as controls. Placental tissue was obtained after inducing labor in fetuses. To identify differential methylation sites (DMSs) and regions (DMRs) in cases vs. controls, an Infinium Human Methylation 850 k bead chip was used. Differential methylation was assessed by comparing the β-values for individual CpG loci. Based on the p-value (<0.05), the most discriminating CpG sites were identified. The area under the receiver-operating-characteristics curve (AUC) was used to determine the predictive accuracy of CpG loci with significant methylation changes for CTDs. The function of genes was assessed through KEGG enrichment analysis, Gene Ontology (GO) analysis, and KEGG pathway analysis. Results: In comparison to the control group, the DNA methylation of the placental tissue is significantly different in fetuses with CTDs. We identified the most significantly different methylated loci and they demonstrated excellent individual predictive accuracy for CTDs detection with AUC >0.9 in cases compared with controls. HOXD9, CNN1, NOTCH1, and ECE1 were identified as CTDs-detection candidate genes. Conclusion Our study established the abnormal changes in placental methylation associated with CTDs and potential epigenetic biomarkers for CTDs detection.
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Abstract Interleukin-36α is a novel member of the IL-1 cytokine family that is highly expressed in epithelial tissues and several myeloid-derived cell types after induction. The transcription factor (TF) C/EBPβ binds specifically to an essential half-CRE•C/EBP motif in the Il36a promoter to induce Il36a expression upon LPS stimulation. C/EBPs regulate gene expression by binding to recognition sequences that can contain 5′-cytosine-phosphate-guanine-3′ dinucleotides (CpG), whose methylation can influence TF binding and gene expression. Herein we show that the half-CRE•C/EBP element in the Il36a promoter is differentially methylated in the murine RAW264.7 macrophage cell line and in primary murine macrophages. We demonstrate that C/EBPβ binding to the half-CRE•C/EBP element in the Il36a promoter following LPS stimulation is insensitive to CpG methylation and that methylation of the CpG in the half-CRE•C/EBP element does not alter LPS-induced Il36a promoter activity which correlated with similar Il36a mRNA copy numbers and pro-IL-36α protein amount in both cell types. Taken together, our data indicate that C/EBPβ binding to the half-CRE•C/EBP element and subsequent gene activation occurs independently of the CpG methylation status of the half-CRE•C/EBP motif and underlines the potential of C/EBPs to recognize methylated as well as unmethylated motifs.
Ccaat-enhancer-binding proteins
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CpG Oligodeoxynucleotide
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