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Methylomic trajectories across human fetal brain development.

ABSTRACT: 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.

SUBMITTER: Spiers H

PROVIDER: S-EPMC4352878 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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Methylomic trajectories across human fetal brain development.

Spiers Helen H Hannon Eilis E Schalkwyk Leonard C LC Smith Rebecca R Wong Chloe C Y CC O'Donovan Michael C MC Bray Nicholas J NJ Mill Jonathan J

Genome research 20150203 3

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. W ...[more]

PMID: 25650246

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Project description:Complicated molecular and cellular processes take place in a spatiotemporally heterogeneous and precisely regulated pattern in the human fetal brain, yielding not only dramatic morphological and microstructural changes, but also macroscale connectomic transitions. As the underlying substrate of the fetal brain structural network, both dynamic neuronal migration pathways and rapid developing fetal white matter (WM) fibers could fundamentally reshape early fetal brain connectome. Quantifying structural connectome development can not only shed light on the brain reconfiguration in this critical yet rarely studied developmental period, but also reveal alterations of the connectome under neuropathological conditions. However, transition of the structural connectome from the mid-fetal stage to birth is not yet known. The contribution of different types of neural fibers to the structural network in the mid-fetal brain is not known, either. In this study, diffusion tensor magnetic resonance imaging (DT-MRI or DTI) of 10 fetal brain specimens at the age of 20 postmenstrual weeks (PMW), 12 in vivo brains at 35 PMW, and 12 in vivo brains at term (40 PMW) were acquired. The structural connectome of each brain was established with evenly parcellated cortical regions as network nodes and traced fiber pathways based on DTI tractography as network edges. Two groups of fibers were categorized based on the fiber terminal locations in the cerebral wall in the 20 PMW fetal brains. We found that fetal brain networks become stronger and more efficient during 20-40 PMW. Furthermore, network strength and global efficiency increase more rapidly during 20-35 PMW than during 35-40 PMW. Visualization of the whole brain fiber distribution by the lengths suggested that the network reconfiguration in this developmental period could be associated with a significant increase of major long association WM fibers. In addition, non-WM neural fibers could be a major contributor to the structural network configuration at 20 PMW and small-world network organization could exist as early as 20 PMW. These findings offer a preliminary record of the fetal brain structural connectome maturation from the middle fetal stage to birth and reveal the critical role of non-WM neural fibers in structural network configuration in the middle fetal stage.

Dataset Information

Methylomic trajectories across human fetal brain development.

Publications

Methylomic trajectories across human fetal brain development.

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