Characterization of the genetic determinants of context-specific DNA methylation in primary monocytes

James J Gilchrist; Hai Fang; Sara Danielli; Marketa Tomkova; Isar Nassiri; Esther Ng; Orion Tong; Chelsea Taylor; Dylan Muldoon; Lea R Z Cohen; Hussein Al-Mossawi; Evelyn Lau; Matt Neville; Benjamin Schuster-Boeckler; Julian C Knight; Benjamin P Fairfax

doi:10.1016/j.xgen.2024.100541

Characterization of the genetic determinants of context-specific DNA methylation in primary monocytes

Cell Genom. 2024 May 8;4(5):100541. doi: 10.1016/j.xgen.2024.100541. Epub 2024 Apr 24.

Authors

Affiliations

¹ Department of Paediatrics, University of Oxford, Oxford OX3 9DU, UK; MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK.
² Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
³ Ludwig Cancer Research Oxford, University of Oxford, Oxford OX3 7DQ, UK.
⁴ MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK; Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
⁵ Nuffield Department of Orthopaedics, Rheumatology, and Musculoskeletal Sciences, University of Oxford, Oxford OX3 7LD, UK.
⁶ MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK.
⁷ Oxford Centre for Diabetes, Endocrinology, and Metabolism, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford OX3 7LE, UK.
⁸ MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK; Department of Oncology, University of Oxford, Oxford OX3 9DS, UK. Electronic address: benjamin.fairfax@oncology.ox.ac.uk.

PMID: 38663408
DOI: 10.1016/j.xgen.2024.100541

Abstract

To better understand inter-individual variation in sensitivity of DNA methylation (DNAm) to immune activity, we characterized effects of inflammatory stimuli on primary monocyte DNAm (n = 190). We find that monocyte DNAm is site-dependently sensitive to lipopolysaccharide (LPS), with LPS-induced demethylation occurring following hydroxymethylation. We identify 7,359 high-confidence immune-modulated CpGs (imCpGs) that differ in genomic localization and transcription factor usage according to whether they represent a gain or loss in DNAm. Demethylated imCpGs are profoundly enriched for enhancers and colocalize to genes enriched for disease associations, especially cancer. DNAm is age associated, and we find that 24-h LPS exposure triggers approximately 6 months of gain in epigenetic age, directly linking epigenetic aging with innate immune activity. By integrating LPS-induced changes in DNAm with genetic variation, we identify 234 imCpGs under local genetic control. Exploring shared causal loci between LPS-induced DNAm responses and human disease traits highlights examples of disease-associated loci that modulate imCpG formation.

Keywords: DNA methylation; LPS; cancer; epigenetic aging; genetics; innate immune activation; mQTL; monocytes.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adult
CpG Islands* / genetics
DNA Methylation* / drug effects
Epigenesis, Genetic* / drug effects
Female
Humans
Lipopolysaccharides* / pharmacology
Male
Monocytes* / drug effects
Monocytes* / immunology
Monocytes* / metabolism

Substances

Lipopolysaccharides