Relating Gene Expression Evolution with CpG Content Changes

Background: Previous studies have shown that CpG dinucleotides are enriched in a subset of promoters and the CpG content of promoters is positively correlated with gene expression levels. But the relationship between divergence of CpG content and gene expression evolution has not been investigated. Here we calculate the normalized CpG (nCpG) content in DNA regions around transcription start site (TSS) and transcription terminal site (TTS) of genes in nine organisms, and relate them with expression levels measured by RNA-seq. Results: The nCpG content of TSS shows a bimodal distribution in all organisms except platypus, whereas the nCpG content of TTS only has a single peak. When the nCpG contents are compared between different organisms, we observe a different evolution pattern between TSS and TTS: compared with TTS, TSS exhibits a faster divergence rate between closely related species but are more conserved between distant species. More importantly, we demonstrate the link between gene expression evolution and nCpG content changes: up-/down- regulation of genes in an organism is accompanied by the nCpG content increase/decrease in their TSS and TTS proximal regions. Conclusions: Our results suggest that gene expression changes between different organisms are correlated with the alterations in normalized CpG contents of promoters. Our analyses provide evidences for the impact of nCpG content on gene expression evolution