Methylomic trajectories across human fetal brain development
Open accessAbstract
Epigenetic processes play a key role in orchestrating transcriptional regulation during development. The importance of DNA methylation in fetal brain development is highlighted by the dynamic expression of de novo DNA methyltransferases during the perinatal period and neurodevelopmental deficits associated with mutations in the methyl-CpG binding protein 2 (MECP2) gene. However, our knowledge about the temporal changes to the epigenome during fetal brain development has, to date, been limited. We quantified genome-wide patterns of DNA methylation at ∼400,000 sites in 179 human fetal brain samples (100 male, 79 female) spanning 23 to 184 d post-conception. We identified highly significant changes in DNA methylation across fetal brain development at >7% of sites, with an enrichment of loci becoming hypomethylated with fetal age. Sites associated with developmental changes in DNA methylation during fetal brain development were significantly underrepresented in promoter regulatory regions but significantly overrepresented in regions flanking CpG islands (shores and shelves) and gene bodies. Highly significant differences in DNA methylation were observed between males and females at a number of autosomal sites, with a small number of regions showing sex-specific DNA methylation trajectories across brain development. Weighted gene comethylation network analysis (WGCNA) revealed discrete modules of comethylated loci associated with fetal age that are significantly enriched for genes involved in neurodevelopmental processes. This is, to our knowledge, the most extensive study of DNA methylation across human fetal brain development to date, confirming the prenatal period as a time of considerable epigenomic plasticity.
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The comparison of our results with sex-specific DNA methylation differences in fetal brain development also showed very little overlap.
“The comparison of our results with sex-specific DNA methylation differences in fetal brain development [88, 89] also showed very little overlap (Additional file 2: Table S19)”
From Sex-specific DNA methylation differences in Alzheimer’s disease pathology (2021) · cites this paper as [88]
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DNA Epigenetics in Addiction Susceptibility
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Contribution of Dopamine Transporter Gene Methylation Status to Cannabis Dependency
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Putative contributions of the sex chromosome proteins SOX3 and SRY to neurodevelopmental disorders
Tahira, A. C., Barbosa, A. R., Feltrin, A. S., Gastaldi, V. D., de Toledo, V. H. C., de Carvalho Pereira, J. G., Lisboa, B. C. G., de Souza Reis, V. N., dos Santos, A. C. F., Maschietto, M., et al. (2019) · American Journal of Medical Genetics Part B: Neuropsychiatric Genetics · doi:10.1002/ajmg.b.32704 · Cited by 11 · see citing works
- Authors
- Spiers, H., Hannon, E., Schalkwyk, L. C., Smith, R., Wong, C. C. Y., O’Donovan, M. C., Bray, N. J., & Mill, J.
- Affiliations
- King's College London (GB)
- University of Exeter (GB)
- University of Essex (GB)
- Cardiff University (GB)
- Corresponding author
- Mill, Jonathan
- ORCID
- Venue
- Genome Research
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2015-02-03
- Volume
- 25
- Issue
- 3
- Pages
- 338-352
- ISSN
- 1088-9051 (ISSN-L)
- 1549-5469
- PMC
- PMC4352878
- OpenAlex
- W2106976893
- Cited by
- 287
- References
- 20
- Citations by year
- 2026: 9 · 2025: 18 · 2024: 21 · 2023: 17 · 2022: 24 · 2021: 41 · 2020: 32 · 2019: 29 · 2018: 24 · 2017: 28 · 2016: 27 · 2015: 16 · 2012: 1
- Type
- posted content
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by
- Locations
- Genome Research (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- ORCA Online Research @Cardiff (Cardiff University) (acceptedVersion)
- Open Access at Essex (University of Essex) (acceptedVersion)
- Research Portal (King's College London) (submittedVersion, cc-by)
- Figshare (submittedVersion)
- Open Research Exeter (University of Exeter) (submittedVersion, cc-by)
- Funders
- Joint MRC (G0700089)
- Wellcome Trust (GR082557)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Syndromes and Imprinting
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- DNA methylation, fetal brain development, human fetal brain, epigenome, CpG islands, gene body methylation, promoter methylation, brain development, MeCP2
- MeSH terms
- Autistic Disorder, Base Composition, Brain, Female, Humans, Male, Pregnancy, Regulatory Sequences, Nucleic Acid, Schizophrenia, Sex Factors, Cluster Analysis, CpG Islands, DNA Methylation, Gene Expression Profiling, Organogenesis, Epigenesis, Genetic, Fetal Development, Genome-Wide Association Study, Epigenomics
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