CpG traffic lights are markers of regulatory regions in human genome

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

Research output: Contribution to journalArticlepeer-review

30 Scopus citations

Abstract

Background:DNA 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. Results:We 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. Conclusions: CpG 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.
Original languageEnglish (US)
JournalBMC Genomics
Volume20
Issue number1
DOIs
StatePublished - Feb 1 2019

Bibliographical note

KAUST Repository Item: Exported on 2020-10-01
Acknowledgements: Acknowledgements:The authors are very grateful to Marina Lizio and Hideya Kawaji for their help with FANTOM5 datasets. Funding:CpG TL detection was supported by RFBR grant 14-04-00180 to YAM. Functional analysis of CpG TL was supported by RFBR grant 17-54-80033 to YAM. AK and VBB were supported by the base research fund of the King Abdullah University of Science and Technology (KAUST). ChIP-Seq data analysis was supported by Russian Science Foundation [17-74-10188 to I.V.K.]. SELEX data analysis was supported the Program of fundamental research for state academies for 2013-2020 years (No 01201363825). These funding bodies had no role in the design of the study, collection, analysis, and interpretation of data, or in writing the manuscript.

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