Passive and active DNA methylation and the interplay with genetic variation in gene regulation

María Gutiérrez‐Arcelus ,Corinne Gehrig,Audrey Letourneau,Halit Ongen,Michel Guipponi,Deborah Bielser,Julien Bryois,Alfonso Buil,Alisa Yurovsky,Emilie Falconnet,Thomas Giger,Tuuli Lappalainen,Alexandra Planchon,Periklis Makrythanasis,Maryline Gagnebin,Christelle Borel,Luciana Romano,Stylianos E Antonarakis ,Ismaël Padioleau ,Stephen B Montgomery ,Emmanouil T Dermitzakis

doi:10.7554/elife.00523

María Gutiérrez‐Arcelus , Corinne Gehrig + Show 19 more

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https://doi.org/10.7554/elife.00523

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Abstract

DNA methylation is an essential epigenetic mark whose role in gene regulation and its dependency on genomic sequence and environment are not fully understood. In this study we provide novel insights into the mechanistic relationships between genetic variation, DNA methylation and transcriptome sequencing data in three different cell-types of the GenCord human population cohort. We find that the association between DNA methylation and gene expression variation among individuals are likely due to different mechanisms from those establishing methylation-expression patterns during differentiation. Furthermore, cell-type differential DNA methylation may delineate a platform in which local inter-individual changes may respond to or act in gene regulation. We show that unlike genetic regulatory variation, DNA methylation alone does not significantly drive allele specific expression. Finally, inferred mechanistic relationships using genetic variation as well as correlations with TF abundance reveal both a passive and active role of DNA methylation to regulatory interactions influencing gene expression. DOI:http://dx.doi.org/10.7554/eLife.00523.001.

Highlights

DNA methylation is an essential (Li et al, 1992) epigenetic mark whose role in gene regulation and its dependency on genomic sequence and environment is not yet fully understood (Jones, 2012; Schubeler, 2012)
We find a significant increased presence of negative compared to positive eQTMs in CTCF binding sites, enhancers and promoters, with this increase being higher in non-CpG island (CGI) promoters compared to CpG islands (CGI) promoters (Figure 2C)
We have shown that inter-individual DNA methylation changes are mechanistically associated to genetic variation and gene expression in complex and context dependent ways that can be of passive or active nature

Summary

Introduction

DNA methylation is an essential (Li et al, 1992) epigenetic mark whose role in gene regulation and its dependency on genomic sequence and environment is not yet fully understood (Jones, 2012; Schubeler, 2012). Mammalian DNA methylation levels are generally high, CpG rich regions, called CpG islands (CGI), appear mostly unmethylated (Bird, 2002; Weber et al, 2007; Lister et al, 2009). Even though it was originally reported to be involved in gene silencing (Holliday and Pugh, 1975; Riggs, 1975), more recent studies have found that DNA methylation can be positively correlated to gene transcription when found in gene bodies (Hellman and Chess, 2007; Lister et al, 2009).

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