Genome-wide identification of genes regulating DNA methylation using genetic anchors for causal inference
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RESEARCH
Open Access
Genome-wide identification of genes regulating DNA methylation using genetic anchors for causal inference Paul J. Hop1,2 , René Luijk1, Lucia Daxinger3, Maarten van Iterson1, Koen F. Dekkers1, Rick Jansen4, BIOS Consortium, Joyce B. J. van Meurs5, Peter A. C. ’t Hoen6, M. Arfan Ikram7, Marleen M. J. van Greevenbroek8,9, Dorret I. Boomsma10, P. Eline Slagboom1, Jan H. Veldink2, Erik W. van Zwet11 and Bastiaan T. Heijmans1* * Correspondence: b.t.heijmans@ lumc.nl 1 Molecular Epidemiology, Department of Biomedical Data Sciences, Leiden University Medical Center, 2333 ZC Leiden, The Netherlands Full list of author information is available at the end of the article
Abstract 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. Keywords: DNA methylation, Epigenetic regulation, Transcription factor, Chromatin, Genetic instrumental variable, Functional genomics, Pleiotropy, Causal inference
Background The epigenome is fundamental to development and cell differentiation. Dysregulation of the epigenome is a hallmark of many diseases, ranging from rare developmental disorders to common complex diseases and aging [1–3]. The epigenome is highly dynamic and is extensively modified and remodeled in response to external and internal stimuli [4]. However, the networks underlying these highly coordinated epigenetic modifications remain to be fully elucidated. Hence, the systematic identification of © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material
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