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© Research
Publication : Genome biology

Exploring the genetic basis of human population differences in DNA methylation and their causal impact on immune gene regulation

Scientific Fields
Diseases
Organisms
Applications
Technique

Published in Genome biology - 18 Dec 2018

Husquin LT, Rotival M, Fagny M, Quach H, Zidane N, McEwen LM, MacIsaac JL, Kobor MS, Aschard H, Patin E, Quintana-Murci L

Link to Pubmed [PMID] – 30563547

Genome Biol. 2018 12;19(1):222

BACKGROUND: DNA methylation is influenced by both environmental and genetic factors and is increasingly thought to affect variation in complex traits and diseases. Yet, the extent of ancestry-related differences in DNA methylation, their genetic determinants, and their respective causal impact on immune gene regulation remain elusive.

RESULTS: We report extensive population differences in DNA methylation between 156 individuals of African and European descent, detected in primary monocytes that are used as a model of a major innate immunity cell type. Most of these differences (~ 70%) are driven by DNA sequence variants nearby CpG sites, which account for ~ 60% of the variance in DNA methylation. We also identify several master regulators of DNA methylation variation in trans, including a regulatory hub nearby the transcription factor-encoding CTCF gene, which contributes markedly to ancestry-related differences in DNA methylation. Furthermore, we establish that variation in DNA methylation is associated with varying gene expression levels following mostly, but not exclusively, a canonical model of negative associations, particularly in enhancer regions. Specifically, we find that DNA methylation highly correlates with transcriptional activity of 811 and 230 genes, at the basal state and upon immune stimulation, respectively. Finally, using a Bayesian approach, we estimate causal mediation effects of DNA methylation on gene expression in ~ 20% of the studied cases, indicating that DNA methylation can play an active role in immune gene regulation.

CONCLUSION: Using a system-level approach, our study reveals substantial ancestry-related differences in DNA methylation and provides evidence for their causal impact on immune gene regulation.

https://www.ncbi.nlm.nih.gov/pubmed/30563547