Methylomic trajectories across human fetal brain development

Helen Spiers (1), Eilis Hannon (2), Leonard C. Schalkwyk (3), Rebecca Smith (1), Chloe C.Y. Wong (1), Michael C. O'Donovan (4), Nicholas J. Bray (1), Jonathan Mill (1,2,*)

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 days 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 under-represented in promoter regulatory regions but significantly over-represented 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 co-methylation network analysis (WGCNA) revealed discrete modules of co-methylated 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. A searchable web-resource of DNA methylation trajectories occurring during fetal brain development is available, see below.

1. Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK
2. University of Exeter Medical School, University of Exeter, Exeter, UK
3. School of Biological Sciences, University of Essex, Colchester, UK
4. MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine, Cardiff, UK

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Table listing all 28,719 Bonferroni-significant fetal brain dDMPs

Table listing all 521 Bonferroni-significant fetal brain autosomal sex dDMPs

Differentially methylated regions (combp method)

Selection of probes from the manuscript