The Regulatory Mechanisms of Intragenic DNA Methylation

Abstract

DNA methylation has crucial roles in gene regulation of mammalian cells. DNA methyltransferases (DNMTs) typically add methyl groups to the cytosine in a CpG dinucleotide context [1]. Approximately 70% of the total number of CpG sites in the mammalian genome are methylated, and intragenic regions account for approximately 40% of methylated CpG sites [2]. However, sites in CpG islands (CGIs), which have an elevated G+C composition, frequently lack DNA methylation and are associated with the promoters of 60% of annotated genes, including promoters of all the housekeeping genes [1]. DNA methylation in promoters generally has a stable gene-silencing effect; however, methylation in intragenic regions is not always associated with gene repression. Currently, the roles of intragenic CGIs are not well defined, but several interesting clues regarding its regulatory functions in gene expression have begun to emerge. For example, intragenic DNA methylation was shown to influence transcriptional elongation and alternative splicing, and abnormal DNA methylation has frequently been associated with cancer progression. To emphasize the importance of intragenic DNA methylation in gene expression, this commentary will discuss its regulatory mechanisms based on recent studies. Interplay between intragenic DNA methylation & H3K4 methylationTo understand the regulatory mechanisms mediated by DNA methylation, the effect of DNA methylation on epigenetic modifications has been examined in the structural contexts of regulated regions. At promoters, the alternating epigenetic modification patterns of DNA and histones are often used as regulatory signals. In particular, promoter-associated CGI modifications are regulated by competitive binding of the CXXC domain of H3K4 methyltransferases and the ADD domain of DNMTs [3]. Unmethylated CGIs typically prefer binding to H3K4 methyltransferases, thus these sequences are highly marked with H3K4me3 and function as active promoter elements. On the other hand, ADD domain binds to nonmethylated lysine 4 residue of histone H3 at unmethylated CGIs, thus the high levels of H3K4me3 marks at CGIs prevent the binding of DNMTs. However, certain CGIs are methylated and considered as repressed, because silenced promoters and compacted heterochromatin regions are often highly methylated. Therefore, DNA methylation and histone H3K4 methylation at CGI promoters result in the opposite transcription activity and prevent the binding of methyltransferases to other types of epigenetic markers. In contrast to the antagonistic relationship with H3K4me3, DNA methylation cooperates with H3K9 methylation to repress promoters via the interaction between DNMT3A/B and G9A H3K9 methyltransferase [2]. These interactions reinforce the promoter-associated DNA methylation as a repressive signature of transcriptional regulation. However, in intragenic regions, these correlations between DNA methylation and transcriptional repression are not observed.The regulatory mechanisms of intragenic DNA methylation " DNA methylation in promo...

Methylation of OPRL1 mediates the effect of psychosocial stress on binge drinking in adolescents

“…Methylation in the promoter area is often negatively correlated with gene expression; however, correlation of methylation in the gene body and cis‐gene expression does not show a specific directionality (Lee, Choi, Lee, & Kim, ). Our findings show that stress‐induced hypomethylation of the Oprl1 gene body in msP rats is associated with a decrease in Oprl1 gene expression.…”

Polymorphism and methylation of the MC4R gene in obese and non-obese dogs

“…Moreover, such hypermethylation may positively correlate with transcription level, in contrast to repression of the expression due to promoter methylation. However, some studies have shown a negative correlation between intragenic methylation and transcriptional elongation [ 32 ] and splicing [ 33 ]. Moreover, there are also observations that DNA methylation interacts with histone modifications and intragenic methylation contributes to proper transcript elongation by removing repressive epigenetic marks (H3K27me3) and recruiting H3K36me3 marks, which are accumulated in actively transcribed units [ 32 ].…”

“…However, some studies have shown a negative correlation between intragenic methylation and transcriptional elongation [ 32 ] and splicing [ 33 ]. Moreover, there are also observations that DNA methylation interacts with histone modifications and intragenic methylation contributes to proper transcript elongation by removing repressive epigenetic marks (H3K27me3) and recruiting H3K36me3 marks, which are accumulated in actively transcribed units [ 32 ]. With regard to the MC4R gene it was shown that methylation of its coding region in mice is influenced by diet [ 19 ].…”

Global DNA methylation profiling uncovers distinct methylation patterns of protocadherin alpha4 in metastatic and non-metastatic rhabdomyosarcoma

“…Advances in genome-wide approaches have demonstrated that methylation varies depending upon the specific genomic context. Although the majority of studies have focused on methylation in the promoter region adjacent to the transcription start site (TSS), methylation of the gene body or intergenic regions seems to have a functional role and contributes to defining the whole picture of the methylation status [33]. …”