Dataset Information

Genome-wide methylation profiling of the bronchial mucosa of asthmatics: relationship to atopy.

ABSTRACT:

Background

Asthma is a common respiratory disease that is characterized by bronchial hyperresponsiveness and airway obstruction due to chronic airway inflammation. Atopic asthma is a typical IgE-mediated disease in which the enhanced production of IgE is driven by the activation of Th2 cells, which release a distinct pattern of cytokines, including interleukin 4 (IL4) and IL3, in response to specific antigen presentation. To evaluate the methylation status of the whole genomes of bronchial mucosa tissues from subjects who lacked or had sensitization to Dermatophagoides farina (Df) and Dermatophagoides pteronyssinus (Dp).

Methods

The genome-wide DNA methylation levels in the bronchial mucosa tissues of atopic asthmatics (N=10), non-atopic asthmatics (N=7), and normal controls (N=7) were examined using microarrays.

Results

In the bronchial mucosa of atopic asthmatics, hypermethylation was detected at 6 loci in 6 genes, while hypomethylation was detected at 49 loci in 48 genes compared to those of non-atopic asthmatics. Genes that were assigned the ontologies of multicellular organismal process, response to organic substance, hormone metabolic process, and growth factor receptor binding were hypomethylated. The methylation levels in the mucosa of asthmatics and normal controls were similar.

Conclusions

The bronchial mucosa of asthmatics who are atopic to Df or Dp have characteristic methylation patterns for 52 genes. The genes and pathways identified in the present study may be associated with the presence of atopy in asthmatics and therefore represent attractive targets for future research.

SUBMITTER: Kim YJ

PROVIDER: S-EPMC3616917 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature

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Publications

Genome-wide methylation profiling of the bronchial mucosa of asthmatics: relationship to atopy.

Kim Yoon-Jeong YJ Park Sung-Woo SW Kim Tae-Hoon TH Park Jong-Sook JS Cheong Hyun Sub HS Shin Hyoung Doo HD Park Choon-Sik CS

BMC medical genetics 20130324

<h4>Background</h4>Asthma is a common respiratory disease that is characterized by bronchial hyperresponsiveness and airway obstruction due to chronic airway inflammation. Atopic asthma is a typical IgE-mediated disease in which the enhanced production of IgE is driven by the activation of Th2 cells, which release a distinct pattern of cytokines, including interleukin 4 (IL4) and IL3, in response to specific antigen presentation. To evaluate the methylation status of the whole genomes of bronchi ...[more]

PMID: 23521807

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Project description:BackgroundThe Indian traditional medicinal system, Ayurveda, describes several lifestyle practices, processes and medicines as an intervention to treat asthma. Rasayana therapy is one of them and although these treatment modules show improvement in bronchial asthma, their mechanism of action, particularly the effect on DNA methylation, is largely understudied.ObjectivesOur study aimed at identifying the contribution of DNA methylation changes in modulating bronchial asthma phenotype upon Ayurveda intervention.Materials and methodsIn this study, genome-wide methylation profiling in peripheral blood DNA of healthy controls and bronchial asthmatics before (BT) and after (AT) Ayurveda treatment was performed using array-based profiling of reference-independent methylation status (aPRIMES) coupled to microarray technique.ResultsWe identified 4820 treatment-associated DNA methylation signatures (TADS) and 11,643 asthma-associated DNA methylation signatures (AADS), differentially methylated [FDR (≤0.1) adjusted p-values] in AT and HC groups respectively, compared to BT group. Neurotrophin TRK receptor signaling pathway was significantly enriched for differentially methylated genes in bronchial asthmatics, compared to AT and HC subjects. Additionally, we identified over 100 differentially methylated immune-related genes located in the promoter/5'-UTR regions of TADS and AADS. Various immediate-early response and immune regulatory genes with functions such as transcription factor activity (FOXD1, FOXD2, GATA6, HOXA3, HOXA5, MZF1, NFATC1, NKX2-2, NKX2-3, RUNX1, KLF11), G-protein coupled receptor activity (CXCR4, PTGER4), G-protein coupled receptor binding (UCN), DNA binding (JARID2, EBF2, SOX9), SNARE binding (CAPN10), transmembrane signaling receptor activity (GP1BB), integrin binding (ITGA6), calcium ion binding (PCDHGA12), actin binding (TRPM7, PANX1, TPM1), receptor tyrosine kinase binding (PIK3R2), receptor activity (GDNF), histone methyltransferase activity (MLL5), and catalytic activity (TSTA3) were found to show consistent methylation status between AT and HC group in microarray data.ConclusionsOur study reports the DNA methylation-regulated genes in bronchial asthmatics showing improvement in symptoms after Ayurveda intervention. DNA methylation regulation in the identified genes and pathways represents the Ayurveda intervention responsive genes and may be further explored as diagnostic, prognostic, and therapeutic biomarkers for bronchial asthma in peripheral blood.

Project description:BackgroundEpigenetic mechanisms could alter the airway epithelial barrier and ultimately lead to atopic diseases such as asthma. We aimed to identify DNA methylation profiles that are associated with-and could accurately classify-atopy and atopic asthma in school-aged children.MethodsWe did a genome-wide study of DNA methylation in nasal epithelium and atopy or atopic asthma in 483 Puerto Rican children aged 9-20 years, recruited using multistage probability sampling. Atopy was defined as at least one positive IgE (≥0·35 IU/mL) to common aeroallergens, and asthma was defined as a physician's diagnosis plus wheeze in the previous year. Significant (false discovery rate p<0·01) methylation signals were correlated with gene expression, and top CpGs were validated by pyrosequencing. We then replicated our top methylation findings in a cohort of 72 predominantly African American children, and in 432 children from a European birth cohort. Next, we tested classification models based on nasal methylation for atopy or atopic asthma in all cohorts.FindingsDNA methylation profiles were markedly different between children with (n=312) and without (n=171) atopy in the Puerto Rico discovery cohort, recruited from Feb 12, 2014, until May 8, 2017. After adjustment for covariates and multiple testing, we found 8664 differentially methylated CpGs by atopy, with false discovery rate-adjusted p values ranging from 9·58 × 10-17 to 2·18 × 10-22 for the top 30 CpGs. These CpGs were in or near genes relevant to epithelial barrier function, including CDHR3 and CDH26, and in other genes related to airway epithelial integrity and immune regulation, such as FBXL7, NTRK1, and SLC9A3. Moreover, 28 of the top 30 CpGs replicated in the same direction in both independent cohorts. Classification models of atopy based on nasal methylation performed well in the Puerto Rico cohort (area under the curve [AUC] 0·93-0·94 and accuracy 85-88%) and in both replication cohorts (AUC 0·74-0·92, accuracy 68-82%). The models also performed well for atopic asthma in the Puerto Rico cohort (AUC 0·95-1·00, accuracy 88%) and the replication cohorts (AUC 0·82-0·88, accuracy 86%).InterpretationWe identified specific methylation profiles in airway epithelium that are associated with atopy and atopic asthma in children, and a nasal methylation panel that could classify children by atopy or atopic asthma. Our findings support the feasibility of using the nasal methylome for future clinical applications, such as predicting the development of asthma among wheezing infants.FundingUS National Institutes of Health.

Project description:Background: DNA methylation aberrations are widespread among the malignant B lymphocytes of patients with chronic lymphocytic leukaemia (CLL), suggesting that DNA methylation might contribute to the pathogenesis of CLL. Aim: We aimed to explore the differentially methylated positions (DMPs) associated with CLL and screen the differentially methylated and expressed genes (DMEGs) by combining public databases. We aimed to observe the direction of each DMEG in CLL based on the DMPs in the promoter and the body region respectively to narrow down DMEGs. We also aimed to explore the methylation heterogeneity of CLL subgroups and the effect of B cells maturation on CLL. Methods: In this population-based case control study, we reported a genome-wide DNA methylation association study using the Infinium HumanMethylation450 BeadChip, profiling the DNA methylation of CD19+ B Cells from 48 CLL cases and 28 healthy controls. By integrating methylation data and expression data from public databases, gene sets were jointly screened, and then the relationship between methylation sites in promoter and body region and expression of each gene was explored. In addition, support vector machine (SVM) classification algorithm was used to identify subgroups of CLL cases based on methylation pattern, and the effect of B-cell differentiation related methylation sites on CLL-related sites was observed. Results: We identified 34,797 DMPs related to CLL across the genome, most of which were hypomethylated; the majority were located in gene body regions. By combining these DMPs with published DNA methylation and RNA sequencing data, we detected 26,244 replicated DMPs associated with 1,130 genes whose expression were significantly different in CLL cases. Among these DMEGs, nine low expressed DMEGs were selected with hypermethylated in promoter and hypomethylated in body region, and 83 high expressed DMEGs were selected with both hypomethylated in promoter and body region. The 48 CLL cases were divided into 3 subgroups based on methylation site by SVM algorithm. Over 92% of CpGs associated with B cell subtypes were found in CLL-related DMPs. Conclusion: The DNA methylation pattern was altered across the genome in CLL patients. The methylation of ZAP70, FMOD, and ADAMTS17 was significantly different between CLL cases and controls. Further studies are warranted to confirm our findings and identify the underlying mechanisms through which these methylation markers are associated with CLL.

Project description:HPV infection results in changes in host gene methylation which, in turn, are thought to contribute to the neoplastic progression of HPV-associated cancers. The objective of this study was to identify joint and disease-specific genome-wide methylation changes in anal and cervical cancer as well as changes in high-grade pre-neoplastic lesions. Formalin-fixed paraffin-embedded (FFPE) anal tissues (n = 143; 99% HPV+) and fresh frozen cervical tissues (n = 28; 100% HPV+) underwent microdissection, DNA extraction, HPV genotyping, bisulfite modification, DNA restoration (FFPE) and analysis by the Illumina HumanMethylation450 Array. Differentially methylated regions (DMR; t test q<0.01, 3 consecutive significant CpG probes and mean Δβ methylation value>0.3) were compared between normal and cancer specimens in partial least squares (PLS) models and then used to classify anal or cervical intraepithelial neoplasia-3 (AIN3/CIN3). In AC, an 84-gene PLS signature (355 significant probes) differentiated normal anal mucosa (NM; n = 9) from AC (n = 121) while a 36-gene PLS signature (173 significant probes) differentiated normal cervical epithelium (n = 10) from CC (n = 9). The CC progression signature was validated using three independent publicly available datasets (n = 424 cases). The AC and CC progression PLS signatures were interchangeable in segregating normal, AIN3/CIN3 and AC and CC and were found to include 17 common overlapping hypermethylated genes. Moreover, these signatures segregated AIN3/CIN3 lesions similarly into cancer-like and normal-like categories. Distinct methylation changes occur across the genome during the progression of AC and CC with overall similar profiles and add to the evidence suggesting that HPV-driven oncogenesis may result in similar non-random methylomic events. Our findings may lead to identification of potential epigenetic drivers of HPV-associated cancers and also, of potential markers to identify higher risk pre-cancerous lesions.

Dataset Information

Genome-wide methylation profiling of the bronchial mucosa of asthmatics: relationship to atopy.

Background

Methods

Results

Conclusions

Publications

Genome-wide methylation profiling of the bronchial mucosa of asthmatics: relationship to atopy.

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