Consistent inverse correlation between DNA methylation of the first intron and gene expression across tissues and species

Abstract

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.Electronic supplementary materialThe online version of this article (10.1186/s13072-018-0205-1) contains supplementary material, which is available to authorized users.

Gene-methylation interactions: Discovering region-wise DNA methylation levels that modify SNP-associated disease risk

“…Therefore, we selected these three regions for our analyses. Importantly, Anastasiadi et al 8 were looking at changes in gene expression associated with changes in DNA methylation distribution within promoters, gene bodies, and gene body sub-regions. Their results showed that in the cases where the association was significant, one could basically use mean or median value instead of looking a the distribution.…”

“…Although the methylation of gene promoters can potentially lead to the suppression of gene expression 1 , it has been shown that certain transcription factors actually require their binding sites to be methylated in order to promote binding 6 . In addition to promoters, DNA methylation within gene enhancer regions and gene bodies might also regulate gene expression 1,[7][8][9] . Thus, the function of DNA methylation is highly region-dependent and may vary from gene to gene.…”

“…We develop the necessary statistical models to estimate the interactions from triad data and discuss critical assumptions that need to be met to avoid false positives. Moreover, we take into account DNA methylation in regions, not single CpG sites, since it has been shown that CpGs act collectively 8,35 .…”

Immune genes,IL1βandCasp9,show sexual dimorphic methylation patterns in the zebrafish gonads

“…Conventionally, higher methylation levels in the gene promoters have been associated with transcriptional silencing (Illingworth and Bird, 2009; Straussman et al, 2009). However, gene expression inhibition have been related to other genomic features like the first exon and the first intron of the gene body not only in human (Blattler et al, 2014) but also in fish (Anastasiadi et al, 2018a). Further, the approach here performed for studying the methylation levels is limited to amplicons about ∼500 bp, that even with the intention of include promotor, first intron and first exon in the targeted regions, the entire gene body and possible enhancers involved in the gene regulation were not fully studied.…”

Genome-wide DNA methylation analysis of heavy cannabis exposure in a New Zealand longitudinal cohort

“…Methylation of cytosine residues within CpG dinucleotides is an important mechanism of variation and regulation in the genome 29–32 . Cytosine methylation, particularly in the promoter region of genes, is often associated with a decrease in transcription 33 , and DNA methylation in the first intron and gene expression is correlated and conserved across tissues and vertebrate species 34 . Furthermore, modulation of methylation at CpG sites within the human genome can result in an epigenetic pattern that is specific to individual environmental exposures, and these may contribute to disease 26; 35–37 .…”