THE FETAL BRAIN EPIGENOME

We have published two manuscripts profiling DNA modifications (DNA methylation and DNA hydroxymethylation) across human fetal brain development; Methylomic trajectories across human fetal brain development (2015) and Trajectories of DNA hydroxymethylation across human brain development(2017). The abstracts for these manuscripts are provided under the Abstracts tab on this page.

You can search the data produced for these publications. See the corresponding tabs to access functions enabling you to;

1. Plot data for individual CpG sites
2. Plot data for all CpG sites associated with a gene
3. Plot data for all CpG sites within a defined genomic region
4. Extract data for specific probes
5. Download tables and figures described in the manuscripts

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.

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

Trajectories of DNA hydroxymethylation across human brain development

Helen Spiers (1), Eilis Hannon (2), Leonard Schalkwyk (3), Nicholas J. Bray (4), Jonathan Mill (1,4)

Epigenetic processes contribute to the regulation of genomic functions that underpin development and differentiation. Recent research from our group found that, as the human brain develops, highly dynamic changes in DNA methylation occur across the genome. This previous study utilised the primary DNA pre-treatment method for quantification of DNA methylation; sodium bisulfite conversion of DNA. It is now recognised that this method does not distinguish DNA methylation from DNA hydroxymethylation, therefore, previously reported DNA methylation measures instead represent total DNA modifications (DNA methylation and DNA hydroxymethylation). Although DNA hydroxymethylation is enriched in the central nervous system little is known about its neurodevelopmental dynamics and broader functional importance, hence, the primary goal of this study was to further characterise the behaviour of DNA hydroxymethylation across human brain development. Using the novel approach of oxidative bisulfite treatment of genomic DNA in conjunction with the Illumina HumanMethylation450 BeadChip, genome-wide levels of DNA hydroxymethylation were quantified in a collection of human fetal brain samples (n = 71; n = 35 male and n = 36 female) spanning 23 to 184 days post-conception (DPC). Bonferroni significant (P < 1.67E-07) changes in DNA hydroxymethylation with fetal brain development were identified at 62 autosomal sites. Applying a discovery significance threshold of P < 5E-05 revealed 2181 autosomal probes associated with fetal brain development, these were enriched for sites displaying decreasing DNA hydroxymethylation with DPC. A total of 32 probes displayed sex-differences in DNA hydroxymethylation at P < 5E-05. Weighted gene co-expression network analysis (WGCNA) identified X discrete modules of co-hydroxymethylated loci associated with fetal DPC that are significantly enriched for genes involved in neurodevelopmental processes. This study represents the first systematic analysis of DNA hydroxymethylation dynamics associated with human fetal brain development.

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

FURTHER INFORMATION