CpG traffic lights are markers of regulatory regions in human genome

Anna V Lioznova,Ivan V Kulakovskiy,Artem V Artemov,Yulia A Medvedeva,Vladimir B Bajic,Vasily Ramensky,Abdullah M Khamis,Elizaveta Besedina

doi:10.1186/s12864-018-5387-1

Abstract

BackgroundDNA methylation is involved in the regulation of gene expression. Although bisulfite-sequencing based methods profile DNA methylation at a single CpG resolution, methylation levels are usually averaged over genomic regions in the downstream bioinformatic analysis.ResultsWe demonstrate that on the genome level a single CpG methylation can serve as a more accurate predictor of gene expression than an average promoter / gene body methylation. We define CpG traffic lights (CpG TL) as CpG dinucleotides with a significant correlation between methylation and expression of a gene nearby. CpG TL are enriched in all regulatory regions. Among all promoters, CpG TL are especially enriched in poised ones, suggesting involvement of DNA methylation in their regulation. Yet, binding of only a handful of transcription factors, such as NRF1, ETS, STAT and IRF-family members, could be regulated by direct methylation of transcription factor binding sites (TFBS) or its close proximity. For the majority of TF, an alternative scenario is more likely: methylation and inactivation of the whole regulatory element indirectly represses functional TF binding with a CpG TL being a reliable marker of such inactivation.ConclusionsCpG TL provide a promising insight into mechanisms of enhancer activity and gene regulation linking methylation of single CpG to gene expression. CpG TL methylation can be used as reliable markers of enhancer activity and gene expression in applications, e.g. in clinic where measuring DNA methylation is easier compared to directly measuring gene expression due to more stable nature of DNA.

Highlights

DNA methylation is involved in the regulation of gene expression
We believe that CpG dinucleotide (CpG) TL provide a promising insight into mechanisms of enhancer activity and gene regulation linking methylation of single CpG to gene expression
To thoroughly investigate the connection between methylation and expression, we focus on methylation levels of single CpG dinucleotides

Summary

Results

CpG traffic lights detection DNA methylation in promoter regions often repress gene expression. At FDR < 0.01 we find only 764/762 genes for which average promoter/gene body methylation correlates with expression, while at the same level of significance we observe 7997 genes correlating significantly with CpG TL methylation levels (Table 1, Additional file 1: Table S1, Table S2). STAT-family and IRF-family binding sites Surprisingly, such GA-rich motifs as those bound by STAT1,2,4 and IRF1,4 are enriched in CpG TL but in their weak positions and in close proximity to the TFBS (Fig. 5h, i, m, n, Additional file 1: Figure S3d-k). Since the enrichment in CpG TL is observed only in weak motif positions we speculate that binding of the TF from STAT- and IRF-families is indirectly affected by methylation of the whole regulatory region

Conclusions

Discussion

Methods