Impacts of Pretranscriptional DNA Methylation, Transcriptional Transcription Factor, and Posttranscriptional microRNA Regulations on Protein Evolutionary Rate

Abstract

Gene expression is largely regulated by DNA methylation, transcription factor (TF), and microRNA (miRNA) before, during, and after transcription, respectively. Although the evolutionary effects of TF/miRNA regulations have been widely studied, evolutionary analysis of simultaneously accounting for DNA methylation, TF, and miRNA regulations and whether promoter methylation and gene body (coding regions) methylation have different effects on the rate of gene evolution remain uninvestigated. Here, we compared human–macaque and human–mouse protein evolutionary rates against experimentally determined single base-resolution DNA methylation data, revealing that promoter methylation level is positively correlated with protein evolutionary rates but negatively correlated with TF/miRNA regulations, whereas the opposite was observed for gene body methylation level. Our results showed that the relative importance of these regulatory factors in determining the rate of mammalian protein evolution is as follows: Promoter methylation ≈ miRNA regulation > gene body methylation > TF regulation, and further indicated that promoter methylation and miRNA regulation have a significant dependent effect on protein evolutionary rates. Although the mechanisms underlying cooperation between DNA methylation and TFs/miRNAs in gene regulation remain unclear, our study helps to not only illuminate the impact of these regulatory factors on mammalian protein evolution but also their intricate interaction within gene regulatory networks.

DNA Methylation within Transcribed Regions

“…The comparative analysis of human DNA methylome data with human-macaque and human-mouse protein evolutionary rates revealed that gene body methylation is negatively correlated with protein evolutionary rate, whereas promoter methylation correlates positively (Chuang and Chiang, 2014). Similarly, genes with heavy body methylation are evolutionarily conserved and enriched for housekeeping functions in invertebrates (Sarda et al, 2012).…”

A-to-I RNA editing contributes to the persistence of predicted damaging mutations in populations

“…In human, it was observed that the majority of gene bodies were heavily methylated (Keller et al 2016). Positiondependent correlations have also been shown between CpG methylation level and d N of the target genes (Chuang and Chiang 2014) or exons (Chuang et al 2012); such methylation-d N correlations were observed to be negative for gene bodies (or internal/last exons) and positive for promoter regions (or first exons). Accordingly, we asked whether our results shown in Figure 5 were biased toward first exons.…”

The evolution of the coding exome of the Arabidopsis species - the influences of DNA methylation, relative exon position, and exon length

“…A follow-up study published lately showed that 65 of 24-nt miRNAs exhibited elevated CHH methylation (but not CpG methylation) around their target sites [31]. These studies imply that miRNA targeting may lead to an increased level of DNA methylation in the gene body of plants (which, in fact, was also observed in human [32]). Of note, nevertheless, each miRNA was predicted to have only one target site in the target gene.…”