The relationship between DNA methylation, genetic and expression inter-individual variation in untransformed human fibroblasts
Open accessAbstract
BACKGROUND: DNA methylation plays an essential role in the regulation of gene expression. While its presence near the transcription start site of a gene has been associated with reduced expression, the variation in methylation levels across individuals, its environmental or genetic causes, and its association with gene expression remain poorly understood. RESULTS: We report the joint analysis of sequence variants, gene expression and DNA methylation in primary fibroblast samples derived from a set of 62 unrelated individuals. Approximately 2% of the most variable CpG sites are mappable in cis to sequence variation, usually within 5 kb. Via eQTL analysis with microarray data combined with mapping of allelic expression regions, we obtained a set of 2,770 regions mappable in cis to sequence variation. In 9.5% of these expressed regions, an associated SNP was also a methylation QTL. Methylation and gene expression are often correlated without direct discernible involvement of sequence variation, but not always in the expected direction of negative for promoter CpGs and positive for gene-body CpGs. Population-level correlation between methylation and expression is strongest in a subset of developmentally significant genes, including all four HOX clusters. The presence and sign of this correlation are best predicted using specific chromatin marks rather than position of the CpG site with respect to the gene. CONCLUSIONS: Our results indicate a wide variety of relationships between gene expression, DNA methylation and sequence variation in untransformed adult human fibroblasts, with considerable involvement of chromatin features and some discernible involvement of sequence variation.
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DNA methylation is associated with both increased and decreased gene expression and other genomic functions including alternative splicing and promoter usage.
“DNA methylation is actually associated with both increased and decreased gene expression (Wagner et al., 2014) and other genomic functions including alternative splicing and promoter usage (Maunakea et al., 2010)”
From DNA methylation meta-analysis reveals cellular alterations in psychosis and markers of treatment-resistant schizophrenia (2021) · cites this paper as Wagner et al., 2014
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- Authors
- Wagner, J. R., Busche, S., Ge, B., Kwan, T., Pastinen, T., & Blanchette, M.
- Affiliations
- McGill University (CA)
- McGill University and Génome Québec Innovation Centre (CA)
- Corresponding author
- Pastinen, Tomi
- Blanchette, Mathieu
- Venue
- Genome biology
- Published
- 2014-02-20
- Volume
- 15
- Issue
- 2
- Pages
- R37-R37
- ISSN
- 1465-6906 (ISSN-L)
- 1474-760X
- PMC
- PMC4053980
- OpenAlex
- W2138848739
- Cited by
- 446
- References
- 40
- Citations by year
- 2026: 12 · 2025: 15 · 2024: 24 · 2023: 16 · 2022: 22 · 2021: 44 · 2020: 37 · 2019: 44 · 2018: 54 · 2017: 52 · 2016: 62 · 2015: 43 · 2014: 20
- FWCI
- 24.21
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Genome biology (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Canadian Institutes of Health Research (111246_1, 120608_1)
- Natural Sciences and Engineering Research Council of Canada
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- DNA methylation, gene expression, interindividual variability, human fibroblasts, cis-eQTL, single nucleotide polymorphisms, allelic expression, Hox genes, chromatin marks, promoter CpG sites, epigenetics
- MeSH terms
- Chromatin, Fibroblasts, Gene Expression Regulation, Humans, Pedigree, Promoter Regions, Genetic, CpG Islands, DNA Methylation, Oligonucleotide Array Sequence Analysis, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Cell Proliferation, Primary Cell Culture
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