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A comparison of gene expression and DNA methylation patterns across tissues and species.

ABSTRACT: Previously published comparative functional genomic data sets from primates using frozen tissue samples, including many data sets from our own group, were often collected and analyzed using nonoptimal study designs and analysis approaches. In addition, when samples from multiple tissues were studied in a comparative framework, individuals and tissues were confounded. We designed a multitissue comparative study of gene expression and DNA methylation in primates that minimizes confounding effects by using a balanced design with respect to species, tissues, and individuals. We also developed a comparative analysis pipeline that minimizes biases attributable to sequence divergence. Thus, we present the most comprehensive catalog of similarities and differences in gene expression and DNA methylation levels between livers, kidneys, hearts, and lungs, in humans, chimpanzees, and rhesus macaques. We estimate that overall, interspecies and inter-tissue differences in gene expression levels can only modestly be accounted for by corresponding differences in promoter DNA methylation. However, the expression pattern of genes with conserved inter-tissue expression differences can be explained by corresponding interspecies methylation changes more often. Finally, we show that genes whose tissue-specific regulatory patterns are consistent with the action of natural selection are highly connected in both gene regulatory and protein-protein interaction networks.

SUBMITTER: Blake LE

PROVIDER: S-EPMC7050529 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundDNA methylation is one of the main epigenetic mechanisms for the regulation of gene expression in eukaryotes. In the standard model, methylation in gene promoters has received the most attention since it is generally associated with transcriptional silencing. Nevertheless, recent studies in human tissues reveal that methylation of the region downstream of the transcription start site is highly informative of gene expression. Also, in some cell types and specific genes it has been found that methylation of the first intron, a gene feature typically rich in enhancers, is linked with gene expression. However, a genome-wide, tissue-independent, systematic comparative analysis of the relationship between DNA methylation in the first intron and gene expression across vertebrates has not been explored yet.ResultsThe most important findings of this study are: (1) using different tissues from a modern fish, we show a clear genome-wide, tissue-independent quasi-linear inverse relationship between DNA methylation of the first intron and gene expression. (2) This relationship is conserved across vertebrates, since it is also present in the genomes of a model pufferfish, a model frog and different human tissues. Among the gene features, tissues and species interrogated, the first intron's negative correlation with the gene expression was most consistent. (3) We identified more tissue-specific differentially methylated regions (tDMRs) in the first intron than in any other gene feature. These tDMRs have positive or negative correlation with gene expression, indicative of distinct mechanisms of tissue-specific regulation. (4) Lastly, we identified CpGs in transcription factor binding motifs, enriched in the first intron, the methylation of which tended to increase with the distance from the first exon-first intron boundary, with a concomitant decrease in gene expression.ConclusionsOur integrative analysis clearly reveals the important and conserved role of the methylation level of the first intron and its inverse association with gene expression regardless of tissue and species. These findings not only contribute to our basic understanding of the epigenetic regulation of gene expression but also identify the first intron as an informative gene feature regarding the relationship between DNA methylation and gene expression where future studies should be focused.

Project description:Osteoarthritis (OA) is a common type of arthritis, which may cause pain and disability. Alterations in gene expression and DNA methylation have been proven to be associated with the development of OA. The aim of the present study was to identify potential therapeutic targets and associated processes for OA via the combined analysis of gene expression and DNA methylation datasets. The gene expression and DNA methylation profiles were obtained from the Gene Expression Omnibus, and differentially expressed genes (DEGs) and differentially methylated sites (DMSs) were identified in the present study, using R programming software. The enriched functions of DEGs and DMSs were obtained via the Database for Annotation, Visualization and Integrated Discovery. Finally, cross analysis of DEGs and DMSs was performed to identify genes that exhibited differential expression and methylation simultaneously. The protein?protein interaction (PPI) network of overlaps between DEGs and DMSs was obtained using the Human Protein Reference Database; the topological properties of PPI network overlaps were additionally obtained. Hub genes in the PPI network were further confirmed via reverse transcription?quantitative polymerase chain reaction (RT?qPCR). The results of the present study revealed that the majority of DEGs and DMSs were upregulated and hypomethylated in patients with OA, respectively. DEGs and DMSs were primarily involved in inflammatory, immune and gene expression regulation?associated processes and pathways. Cross analysis revealed 30 genes that exhibited differential expression and methylation in OA simultaneously. Topological analysis of the PPI network revealed that numerous genes, including G protein subunit ?1 (GNAI1), runt related transcription factor 2 (RUNX2) and integrin subunit ?2 (ITGB2), may be involved in the development of OA. Additionally, RT?qPCR analysis of GNAI1, RUNX2 and ITGB2 provided further confirmation. Numerous known and novel therapeutic targets were obtained via network analysis. The results of the present study may be beneficial for the diagnosis and treatment of OA.

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A comparison of gene expression and DNA methylation patterns across tissues and species.

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