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

Autor:	Gilchrist JJ; Department of Paediatrics, University of Oxford, Oxford OX3 9DU, UK; MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK., Fang H; Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK., Danielli S; Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK., Tomkova M; Ludwig Cancer Research Oxford, University of Oxford, Oxford OX3 7DQ, UK., Nassiri I; MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK; Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK., Ng E; Nuffield Department of Orthopaedics, Rheumatology, and Musculoskeletal Sciences, University of Oxford, Oxford OX3 7LD, UK., Tong O; MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK., Taylor C; MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK., Muldoon D; MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK., Cohen LRZ; MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK., Al-Mossawi H; Nuffield Department of Orthopaedics, Rheumatology, and Musculoskeletal Sciences, University of Oxford, Oxford OX3 7LD, UK., Lau E; Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK., Neville M; Oxford Centre for Diabetes, Endocrinology, and Metabolism, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford OX3 7LE, UK., Schuster-Boeckler B; Ludwig Cancer Research Oxford, University of Oxford, Oxford OX3 7DQ, UK., Knight JC; Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK., Fairfax BP; 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.
Jazyk:	angličtina
Zdroj:	Cell genomics [Cell Genom] 2024 May 08; Vol. 4 (5), pp. 100541. Date of Electronic Publication: 2024 Apr 24.
DOI:	10.1016/j.xgen.2024.100541
Abstrakt:	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. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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