scholarly journals Combined Analysis of the Aberrant Epigenetic Alteration of Pancreatic Ductal Adenocarcinoma

2019 ◽  
Vol 2019 ◽  
pp. 1-11
Author(s):  
Rui Xu ◽  
Qiuyan Xu ◽  
Guanglei Huang ◽  
Xinhai Yin ◽  
Jianguo Zhu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Pathway Analysis ◽  
Differential Methylation ◽  
Ductal Adenocarcinoma ◽  
Integrated Analysis ◽  
Epigenetic Alteration ◽  
Differentially Methylated Genes ◽  
Aberrant Dna Methylation

Background. Pancreatic ductal adenocarcinoma (PDAC) remains one of the most fatal malignancies due to its high morbidity and mortality. DNA methylation exerts a vital part in the development of PDAC. However, a mechanistic role of mutual interactions between DNA methylation and mRNA as epigenetic regulators on transcriptomic alterations and its correlation with clinical outcomes such as survival have remained largely uncovered in cancer. Therefore, elucidation of aberrant epigenetic alteration in the development of PDAC is an urgent problem to be solved. In this work, we conduct an integrative epigenetic analysis of PDAC to identify aberrant DNA methylation-driven cancer genes during the occurrence of cancer. Methods. DNA methylation matrix and mRNA profile were obtained from the TCGA database. The integration of methylation and gene expression datasets was analyzed using an R package MethylMix. The genes with hypomethylation/hypermethylation were further validated in the Kaplan–Meier analysis. The correlation analysis of gene expression and aberrant DNA methylation was also conducted. We performed a pathway analysis on aberrant DNG methylation genes identified by MethylMix criteria using ConsensusPathDB. Results. 188 patients with both methylation data and mRNA data were considered eligible. A mixture model was constructed, and differential methylation genes in normal and tumor groups using the Wilcoxon rank test was performed. With the inclusion criteria, 95 differential methylation genes were detected. Among these genes, 74 hypermethylation and 21 hypomethylation genes were found. The pathway analysis revealed an increase in hypermethylation of genes involved in ATP-sensitive potassium channels, Robo4, and VEGF signaling pathways crosstalk, and generic transcription pathway. Conclusion. Integrated analysis of the aberrant epigenetic alteration in pancreatic ductal adenocarcinoma indicated that differentially methylated genes could play a vital role in the occurrence of PDAC by bioinformatics analysis. The present work can help clinicians to elaborate on the function of differentially methylated expressed genes and pathways in PDAC. CDO1, GJD2, ID4, NOL4, PAX6, TRIM58, and ZNF382 might act as aberrantly DNA-methylated biomarkers for early screening and therapy of PDAC in the future.

scholarly journals Altered DNA methylation in ion transport and immune signalling genes is associated with severity in Pancreatic Ductal Adenocarcinoma

2021 ◽  
Author(s):  
Ankita Chatterjee ◽  
Akash Bararia ◽  
Debopriyo Ganguly ◽  
Paromita Roy ◽  
Sudeep Banerjee ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Pancreatic Tissue ◽  
Differential Methylation ◽  
Ductal Adenocarcinoma ◽  
P Value ◽  
Tissue Samples ◽  
Normal Tissues ◽  
Transcription Regulators

Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the leading cancers worldwide and has a poor survival, with a relative five-year survival rate of only 8.5%. In this study we investigated epigenetic marks associated with PDAC severity and prognosis, through studying alterations in DNA methylation patterns. Methods: DNA methylome for tumor and adjacent normal tissue samples from PDAC patients (n=7) were generated using Illumina 450K bead chips. Differentially methylated positions (DMPs) were identified with |delta beta| > 0.2 and p-value<0.01 by comparing tumors with the adjacent normal tissues. Validation of differential methylation and associated gene expression at selected genes was carried out in an independent cohort PDAC patient. Results: We identified 76 DMPs in PDAC patients that mapped to 43 genes. Among them, 44.7% (n=34) were hypo-methylated and 55.3% (n=42) were hyper-methylated DMPs in cancer samples. The trends of change in methylation at these 76 DMPs from well to moderate were like that from moderate to poorly differentiated cancer samples. The gradual trend in differential methylation was observed both in our cohort and the TCGA-PAAD cohort, suggesting methylation marks can serve as early indicators of disease pathology. Altered promoter methylation, which may affect gene expression, was observed for transcription regulators (BHLHE23, GSC2, FOXE1 and TWIST1), gated ion channels (KCNA6, and CACNB2), tumor suppressors (RASSF1, SPRED2, and NPY) and genes functioning in interferon signalling (SIGIRR, MX2, and OAS2). We also have compared the TCGA-PAAD dataset with normal pancreatic tissue data from GTEx V8 dataset leading to a confluent observation. Conclusions: We reported the first study on methylome in PDAC tumors from patients in India. We identified altered DNA methylation associated with increasing severity in PDAC among some genes like SIGIRR, MX2 along with other previously reported loci. We also concluded a confluence in our observation when comparing the TCGA-PAAD dataset with GTEx V8 dataset.

scholarly journals Integrated Analysis of Methylome and Transcriptome Following Developmental Atrazine Exposure in Zebrafish Reveals Aberrant Gene-Specific Methylation of Neuroendocrine and Reproductive Pathways

2020 ◽  
Author(s):  
Chris Bryan ◽  
Li Lin ◽  
Junkai Xie ◽  
Janiel Ahkin Chin Tai ◽  
Katharine A. Horzmann ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Molecular Mechanisms ◽  
The United States ◽  
Integrated Analysis ◽  
Aberrant Methylation ◽  
Morphological Alterations ◽  
Differentially Methylated Genes ◽  
Genome Bisulfite Sequencing ◽  
Aberrant Gene

ABSTRACTAtrazine (ATZ) is one of the most commonly used herbicides in the United States. Previous studies have hypothesized the role of ATZ as an endocrine disruptor (EDC), and developmental exposure to ATZ has been shown to lead to behavioral and morphological alterations. Specific epigenetic mechanisms responsible for these alterations, however, are yet to be elucidated. In this study, we exposed zebrafish embryos to 0.3, 3, and 30 ppb (µg/L) of ATZ for 72 hours post fertilization. We performed whole-genome bisulfite sequencing (WGBS) to assess the effects of developmental ATZ exposure on DNA methylation in female fish brains. The number of differentially methylated genes (DMG) increase with increasing dose of treatments. DMGs are enriched in neurological pathways with extensive methylation changes consistently observed in neuroendocrine and reproductive pathways. To assess the effects of DNA methylation on gene expression, we integrated our data with transcriptomic data. Four genes, namely CHD9, FRAS1, PID1, and PCLO, were differentially expressed and methylated in each dose. Overall, this study identifies specific genes and pathways with aberrant methylation and expression following ATZ exposure as targets to elucidate the molecular mechanisms of ATZ toxicity and presents ATZ-induced site-specific DNA methylation as a potential mechanism driving aberrant gene expression.

scholarly journals Network analyses of circular RNAs expression profiles and their hub genes in pancreatic ductal adenocarcinoma

2019 ◽  
Author(s):  
Yanyan Tang ◽  
Ping Zhang
Keyword(s):  
Gene Expression ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Signaling Pathway ◽  
Pathway Analysis ◽  
Kegg Pathway ◽  
Expression Profiles ◽  
Ductal Adenocarcinoma ◽  
Ppi Network ◽  
Hub Genes ◽  
Kegg Pathway Analysis

Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the most common malignant tumor in digestive system. CircRNAs involve in lots of biological processes through interacting with miRNAs and their targeted mRNA. We obtained the circRNA gene expression profiles from Gene Expression Omnibus (GEO) and identified differentially expressed genes (DEGs) between PDAC samples and paracancerous tissues. Bioinformatics analyses, including GO analysis, KEGG pathway analysis and PPI network analysis, were conducted for further investigation. We also constructed circRNA‑microRNA-mRNA co-expression network. A total 291 differentially expressed circRNAs were screened out. The GO enrichment analysis revealed that up-regulated DEGs were mainly involved metabolic process, biological regulation, and gene expression, and down-regulated DEGs were involved in cell communication, single-organism process, and signal transduction. The KEGG pathway analysis, the upregulated circRNAs were enriched cGMP-PKG signaling pathway, and HTLV-I infection, while the downregulated circRNAs were enriched in protein processing in endoplasmic reticulum, insulin signaling pathway, regulation of actin cytoskeleton, etc. Four genes were identified from PPI network as both hub genes and module genes, and their circRNA‑miRNA-mRNA regulatory network also be constructed. Our study indicated possible involvement of dysregulated circRNAs in the development of PDAC and promoted our understanding of the underlying molecular mechanisms.

scholarly journals A novel epigenetic signature for predicting the prognosis of pancreatic ductal adenocarcinoma

2020 ◽  
Author(s):  
Zhiming Zhao ◽  
Mengyang Li ◽  
Xianglong Tan ◽  
Rong Liu
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Regression Analysis ◽  
Survival Analysis ◽  
Prognostic Factors ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Cox Regression ◽  
Risk Groups ◽  
Ductal Adenocarcinoma ◽  
Cox Regression Analysis

Abstract Background Aberrant DNA methylation is often involved in carcinogenesis. This study is designed to establish an epigenetic signature to predict overall survival (OS) of pancreatic ductal adenocarcinoma (PDAC). Methods DNA methylation and RNA-seq data of PDAC patients were downloaded from the Cancer Genome Atlas database, Genotype-Tissue Expression (GTEx), and International Cancer Genome Consortium (ICGC) database. Methylation-related differentially expressed genes (DEGs) were identified using an R package MethylMix. Epigenetic signature and nomogram were established by the LASSO and multivariate Cox regression analysis, respectively. In addition, a joint survival analysis of the gene expression and methylation was performed to identify potential prognostic factors for patients with PDAC. Results There were a total of 56 methylation-related DEGs by MethylMix criteria. After LASSO Cox regression analysis, we developed an epigenetic signature composed of five genes according to their methylation level. The signature was able to divide patients into high-risk and low-risk groups, and the OS between the high-and low-risk groups was more significantly different in both training and validation cohort. The signature is independent of clinicopathological variables and indicated better predictive power. Moreover, we developed a novel prognostic nomogram that combines risk scores with three clinicopathological factors. The joint survival analysis of gene expression and methylation revealed that 24 genes could be independent prognostic factors for OS in PDAC. Conclusions The qualitative signature and nomogram that predict OS at the individualized level and guide therapy for patients with PDAC.

scholarly journals Cellular Heterogeneity–Adjusted cLonal Methylation (CHALM) improves prediction of gene expression

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Jianfeng Xu ◽  
Jiejun Shi ◽  
Xiaodong Cui ◽  
Ya Cui ◽  
Jingyi Jessica Li ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Cellular Heterogeneity ◽  
Biological Functions ◽  
Global Correlation ◽  
Differentially Methylated Genes ◽  
Promoter Dna Methylation ◽  
Functional Consequences ◽  
Promoter Dna ◽  
Underlying Mechanisms

AbstractPromoter DNA methylation is a well-established mechanism of transcription repression, though its global correlation with gene expression is weak. This weak correlation can be attributed to the failure of current methylation quantification methods to consider the heterogeneity among sequenced bulk cells. Here, we introduce Cell Heterogeneity–Adjusted cLonal Methylation (CHALM) as a methylation quantification method. CHALM improves understanding of the functional consequences of DNA methylation, including its correlations with gene expression and H3K4me3. When applied to different methylation datasets, the CHALM method enables detection of differentially methylated genes that exhibit distinct biological functions supporting underlying mechanisms.

scholarly journals Aberrant DNA methylation associated with silencing BNIP3 gene expression in haematopoietic tumours

2005 ◽  
Vol 92 (6) ◽  
pp. 1165-1172 ◽  
Author(s):  
M Murai ◽  
M Toyota ◽  
A Satoh ◽  
H Suzuki ◽  
K Akino ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Aberrant Dna Methylation

Frequent Alterations Of Hox Family Gene Expression Via Aberrant DNA Methylation In Benign And Malignant Parathyroid Tumors

2011 ◽  
Vol 165 (2) ◽  
pp. 295-296
Author(s):  
L.F. Starker ◽  
T. Ūerstrup ◽  
G. Westin ◽  
P. Hellman ◽  
R. Udelsman ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Parathyroid Tumors ◽  
Family Gene ◽  
Aberrant Dna Methylation

scholarly journals Cadmium-associated differential methylation throughout the placental genome: epigenome-wide association study of two US birth cohorts

2017 ◽  
Author(s):  
Todd M. Everson ◽  
Tracy Punshon ◽  
Brian P. Jackson ◽  
Ke Hao ◽  
Luca Lambertini ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Fetal Development ◽  
Meta Analysis ◽  
Reproductive Toxicity ◽  
Differential Methylation ◽  
Cellular Growth ◽  
Birth Cohorts ◽  
Inflammatory Signaling ◽  
P Values

AbstractBackgroundCadmium (Cd) is a ubiquitous toxicant that during pregnancy can impair fetal development. Cd sequesters in the placenta where it can impair placental function, impacting fetal development. We aimed to investigate Cd-associated variations in placental DNA methylation (DNAM), associations with gene expression, and identify novel pathways involved in Cd-associated reproductive toxicity.MethodsUsing placental DNAM and Cd concentrations in the New Hampshire Birth Cohort Study (NHBCS, n=343) and the Rhode Island Child Health Study (RICHS, n=141), we performed an EWAS between Cd and DNAM, adjusting for tissue heterogeneity using a reference-free method. Cohort-specific results were aggregated via inverse variance weighted fixed effects meta-analysis, and variably methylated CpGs were associated with gene expression. We then performed functional enrichment analysis and tests for associations between gene expression and birth metrics.ResultsWe identified 17 Cd-associated differentially methylated CpG sites with meta-analysis p-values < 1e-05, two of which were within a 5% false discovery rate (FDR). Methylation levels at 9 of the 17 loci were associated with increased expression of 6 genes (5% FDR): TNFAIP2, EXOC3L4, GAS7, SREBF1, ACOT7, and RORA. Higher placental expression of TNFAIP2 and ACOT7, and lower expression of RORA, were associated with lower birth weight z-scores (p-values < 0.05).ConclusionCd associated differential DNAM and corresponding DNAM-expression associations at these loci are involved in inflammatory signaling and cell growth. The expression levels of genes involved in inflammatory signaling (TNFAIP2, ACOT7, and RORA), were also associated with birth metrics, suggesting a role for inflammatory processes in Cd-associated reproductive toxicity.SignificanceCadmium is a toxic environmental pollutant that can impair fetal development. The mechanisms underlying this toxicity are unclear, though disrupted placental functions could play an important role. In this study we examined associations between cadmium concentrations and DNA methylation throughout the placental genome, across two US birth cohorts. We observed cadmium-associated differential methylation, and corresponding methylation-expression associations at genes involved in cellular growth processes and/or immune and inflammatory signaling. This study provides supporting evidence that disrupted placental epigenetic regulation of cellular growth and immune/inflammatory signaling could play a role in cadmium associated reproductive toxicity in human pregnancies.

Abstract 500: DNA Methylation Profiling Reveals an Epithelial/Endothelial-Mesenchymal Transition-like Signature of Intima-Media Cells in the Ascending Aorta of Bicuspid Aortic Valve Patients

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Hanna M Björck ◽  
Lei Du ◽  
Valentina Paloschi ◽  
Shohreh Maleki ◽  
Silvia Pulignani ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Epithelial Mesenchymal Transition ◽  
Ascending Aorta ◽  
Molecular Signature ◽  
Aortic Valves ◽  
Global Methylation ◽  
Mesenchymal Transition ◽  
Differentially Methylated Genes ◽  
Increased Risk

Introduction: Individuals with bicuspid aortic valves (BAV) are at increased risk of ascending aortic aneurysm than individuals with tricuspid aortic valves (TAV), but the underlying mechanism is not fully understood. Aberrant DNA methylation has been described in various human diseases, and we have shown that key enzymes in the methylation machinery are differentially expressed in the aortic intima-media of BAV and TAV patients. In the present study, we assessed the hypothesis that DNA methylation may play an important role during aneurysm formation in BAV. We undertook a global methylation approach to delineate biological processes associated with BAV aortopathy, using TAV as a reference. Methods: Ascending aortic biopsies were collected from 21 BAV and 24 TAV patients, with either a non-dilated or a dilated aorta, at the time of surgery. Global DNA methylation was measured in the intima-media layer using Illumina 450k Array. Gene expression was analyzed in the same samples using Affymetrix Exon Array. Results: Compared with TAV, the BAV dilated aorta was hypomethylated (P=0.031), correlating with an up-regulation of global gene expression. A total of 4913 differentially methylated regions (DMRs) were identified and Hallmark analysis of the DMR-associated genes with a fold change of 10% (n=3147) showed a gene signature of Epithelial Mesenchymal Transition (EMT) (FDR q=2.91e-29). This was further confirmed by functional annotation analysis of hypomethylated DMRs using the Genomic Regions Enrichment of Annotations Tool (Stanford University), showing association to actin filament bundle (P=7.09e-12), stress fibers (P=1.72e-11) and adherence junctions (P=2.97e-8). Interestingly, analysis of non-dilated BAV and TAV aorta revealed that genes involved in EMT were the most differentially methylated genes prior to dilatation (FDR q=1.18e-6). We further confirmed the EMT-related molecular signature by immunostaining of some key players of EMT. In conclusion, epigenetic profiling clearly revealed differential methylation between BAV and TAV aorta, particularly in EMT-related genes. Aberrant EMT in the ascending aorta prior to dilatation may constitute the basis for the increased aneurysm susceptibility in BAV patients.

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