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Genome?wide analysis of DNA methylation and gene expression changes in an ovalbumin?induced asthma mouse model.

ABSTRACT: The aim of the present study was to establish an integrated network of DNA methylation and RNA expression in an ovalbumin (OVA)?induced asthma model, and to investigate the epigenetically?regulated genes involved in asthma development. Genome?wide CpG?DNA methylation profiling was conducted through the use of a methylated DNA immunoprecipitation microarray and RNA sequencing was performed using three lung samples from mice with OVA?induced asthma. A total of 35,401 differentially methylated regions (DMRs) were identified between mice with OVA?induced asthma and control mice. Of these, 3,060 were located in promoter regions and 370 of the genes containing these DMRs demonstrated an inverse correlation between methylation and gene expression. Kyoto Encyclopedia of Genes and Genomes pathway analysis identified that 368 genes were upregulated or downregulated in OVA?induced asthma samples, including genes involved in 'chemokine signalling pathway', 'focal adhesion', 'leukocyte transendothelial migration' and 'vascular smooth muscle contraction signaling' pathways. Integrated network analysis identified four hub genes, consisting of three upregulated genes [forkhead box O1 (FOXO1), SP1 transcription factor (SP1) and amyloid ? precursor protein (APP)], and one downregulated gene [RUNX family transcription factor 1 (RUNX1)], all of which demonstrated an association between DNA methylation and gene expression. These genes were highly interconnected nodes in the Ingenuity Pathway Analysis module and were functionally significant. A total of four interconnected hub genes, FOXO1, RUNX1, SP1 and APP, were identified from the integrated DNA methylation and gene expression networks involved in asthma development. These results suggested that modulating these four genes could effectively control the development of asthma.

SUBMITTER: Kim JS

PROVIDER: S-EPMC7411290 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Genome‑wide analysis of DNA methylation and gene expression changes in an ovalbumin‑induced asthma mouse model.

Kim Joong-Sun JS Shin In-Sik IS Shin Na-Rae NR Nam Jae-Yong JY Kim Chul C

Molecular medicine reports 20200617 3

The aim of the present study was to establish an integrated network of DNA methylation and RNA expression in an ovalbumin (OVA)‑induced asthma model, and to investigate the epigenetically‑regulated genes involved in asthma development. Genome‑wide CpG‑DNA methylation profiling was conducted through the use of a methylated DNA immunoprecipitation microarray and RNA sequencing was performed using three lung samples from mice with OVA‑induced asthma. A total of 35,401 differentially methylated regi ...[more]

PMID: 32705270

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Project description:BackgroundEarly life is a period of drastic epigenetic remodeling in which the epigenome is especially sensitive to extrinsic and intrinsic influence. However, the epigenome-wide dynamics of the DNA methylation changes that occur during this period have not been sufficiently characterized in longitudinal studies.MethodsTo this end, we studied the DNA methylation status of more than 750,000 CpG sites using Illumina MethylationEPIC arrays on 33 paired blood samples from 11 subjects at birth and at 5 and 10 years of age, then characterized the chromatin context associated with these loci by integrating our data with histone, chromatin-state and enhancer-element external datasets, and, finally, validated our results through bisulfite pyrosequencing in two independent longitudinal cohorts of 18 additional subjects.ResultsWe found abundant DNA methylation changes (110,726 CpG sites) during the first lustrum of life, while far fewer alterations were observed in the subsequent 5 years (460 CpG sites). However, our analysis revealed persistent DNA methylation changes at 240 CpG sites, indicating that there are genomic locations of considerable epigenetic change beyond immediate birth. The chromatin context of hypermethylation changes was associated with repressive genomic locations and genes with developmental and cell signaling functions, while hypomethylation changes were linked to enhancer regions and genes with immunological and mRNA and protein metabolism functions. Significantly, our results show that genes that suffer simultaneous hyper- and hypomethylation are functionally distinct from exclusively hyper- or hypomethylated genes, and that enhancer-associated methylation is different in hyper- and hypomethylation scenarios, with hypomethylation being more associated to epigenetic changes at blood tissue-specific enhancer elements.ConclusionsThese data show that epigenetic remodeling is dramatically reduced after the first 5 years of life. However, there are certain loci which continue to manifest DNA methylation changes, pointing towards a possible functionality beyond early development. Furthermore, our results deepen the understanding of the genomic context associated to hyper- or hypomethylation alterations during time, suggesting that hypomethylation of blood tissue-specific enhancer elements could be of importance in the establishment of functional states in blood tissue during early-life.

Dataset Information

Genome?wide analysis of DNA methylation and gene expression changes in an ovalbumin?induced asthma mouse model.

Publications

Genome‑wide analysis of DNA methylation and gene expression changes in an ovalbumin‑induced asthma mouse model.

Similar Datasets

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