Methylomic trajectories across human fetal brain development

• DOI: 10.1101/gr.180273.114
• Publication Date: 2015-02-04T04:28:27Z
• Authors: Helen Spiers; Eilis Hannon; Leonard C. Schalkwyk; Rebecca Smith; Chloe C.Y. Wong; Michael C. O’Donovan; Nicholas J. Bray; Jonathan Mill
• Keywords: Epigenomics; Male; 0301 basic medicine; 570; RJ; QH301 Biology; Organogenesis; 610; Regulatory Sequences, Nucleic Acid; Epigenesis, Genetic; Fetal Development; 03 medical and health sciences; Sex Factors; Genetic; Pregnancy; Cluster Analysis; Humans; Autistic Disorder; QH426; Base Composition; Nucleic Acid; Research; Gene Expression Profiling; Brain; DNA Methylation; R1; RC0321; Schizophrenia; CpG Islands; Female; Regulatory Sequences; Epigenesis; Genome-Wide Association Study

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.