Background
DNA methylation is a key epigenetic modification in human development and disease, yet there is limited understanding of its highly coordinated regulation. Here, we identify 818 genes that affect DNA methylation patterns in blood using large-scale population genomics data.
Results
By employing genetic instruments as causal anchors, we establish directed associations between gene expression and distant DNA methylation levels, while ensuring specificity of the associations by correcting for linkage disequilibrium and pleiotropy among neighboring genes. The identified genes are enriched for transcription factors, of which many consistently increased or decreased DNA methylation levels at multiple CpG sites. In addition, we show that a substantial number of transcription factors affected DNA methylation at their experimentally determined binding sites. We also observe genes encoding proteins with heterogenous functions that have widespread effects on DNA methylation, e.g., NFKBIE, CDCA7(L), and NLRC5, and for several examples, we suggest plausible mechanisms underlying their effect on DNA methylation.
Conclusion
We report hundreds of genes that affect DNA methylation and provide key insights in the principles underlying epigenetic regulation.
Overview publication
Title | Genome-wide identification of genes regulating DNA methylation using genetic anchors for causal inference. |
Date | August 28th, 2020 |
Issue name | Genome biology |
Issue number | v21.1:220 |
DOI | 10.1186/s13059-020-02114-z |
PubMed | 32859263 |
Authors | |
Info | BIOS Consortium, Heijmans BT, 't Hoen PAC, van Meurs J, Jansen R, Franke L, Boomsma DI, Pool R, van Dongen J, Hottenga JJ, van Greevenbroek MMJ, Stehouwer CDA, van der Kallen CJH, Schalkwijk CG, Wijmenga C, Zhernakova S, Tigchelaar EF, Slagboom PE, Beekman M, Deelen J, van Heemst D, Veldink JH, van den Berg LH, van Duijn CM, Isaacs A, Uitterlinden AG, Jhamai PM, Verbiest M, Suchiman HED, Verkerk M, van der Breggen R, van Rooij J, Lakenberg N, Mei H, van Iterson M, Zhernakova DV, van 't Hof P, Deelen P, 't Hoen PAC, Vermaat M, Luijk R, Bonder MJ, van Dijk F, Arindrarto W, Kielbasa SM, van Zwet EW, 't Hoen PB |
Keywords | Causal inference, Chromatin, DNA methylation, Epigenetic regulation, Functional genomics, Genetic instrumental variable, Pleiotropy, Transcription factor |
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