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Researchers Characterize Fetal Brain Methylome, Detect Sex Differences

NEW YORK (GenomeWeb) – DNA methylation patterns change as the fetal brain develops, and some of those changes appear to be sex-specific, according to an epigenome study performed by a UK-based team of researchers.

As they reported in Genome Research, researchers led by the University of Exeter Medical School and King's College London's Jonathan Mill examined the methylation status of some 400,000 sites in nearly 180 fetal brain samples ranging in age from 23 days to 184 days post-conception.

There were significant DNA methylation changes at more than 7 percent of sites investigated during fetal development, the researchers reported, with sites tending to become less methylated as development progressed.

"The prenatal period is a time of dramatic plasticity, when the brain is laying down the structures that control neurobiological function across life," Mill said in a statement.

As some neuropsychiatric disorders are thought to have developmental roots and have susceptibility differences by sex, the researchers also examined whether any of these differentially methylated sites were near autism- or schizophrenia-linked loci.

"Understanding the way in which genes are activated during this important period in the brain could teach us about the origins of disorders with a neurodevelopmental component, such as autism and schizophrenia," Mill added.

To study the fetal brain epigenome, he and his colleagues examined DNA methylation patterns of 100 male and 79 female fetal brain samples using the Illumina Infinium HumanMethylation450 BeadChip.

Global levels of DNA methylation, they reported, didn't change much during fetal brain development, though levels at some 28,700 individual sites did vary.

Overall, these developmentally differentially methylated sites became hypomethylated as fetal age increased and development progressed. Many of the developmentally differentially methylated positions the researchers identified were located near genes known to have a role in neurodevelopment, such as SFRP1, NR4A2, and SHANK2.

More than 8,000 sites, though, were differentially methylated between male and female samples, Mill and his colleagues said. Most of these sites, they noted, are on the X chromosome and are likely involved in in X chromosome dosage compensation.

But about 6.5 percent of the sites could be traced to autosomal locations, about half of which were hypermethylated. Of these differentially methylated autosomal sites, nearly a quarter overlapped with methylation differences found in a previous study of adult brains from men and women, suggesting that some of these differences may be life long.

The researchers further identified 61 sites that follow the same sex-specific DNA methylation trajectory across brain development. Among these, the top-ranked autosomal sex-specific developmentally differentially methylated site was within the gene body of RBPJ, which encodes a transcriptional regulator in the Notch signaling pathways that's involved in neurogenesis and neuronal maturation. It starts out highly methylated in both males and females at the onset of development, but around 100 days post-conception, the site in females becomes hypomethylated.

This timing, the researchers noted, coincides with a testosterone peak that's thought to mediate sexual differentiation of the brain.

Mill and his colleagues also examined whether any of these developmentally differentially methylated positions were near loci linked to disorders like autism and schizophrenia that have neurodevelopmental origins and differences in susceptibility between men and women.

The researchers found that a number of genomic regions linked to schizophrenia and to autism contained multiple developmentally differentially methylated positions, suggesting possible clues as to the positions of functional variants linked to those disorders.

"Understanding sex differences in brain development may help us understand the origins of these differences," first author Helen Spiers from King's College London added.

The researchers also cautioned that their study was restricted to earlier stages of fetal development and, because of how the tissue samples were collected, didn't analyze brain regions separately.