The developing brain undergoes rapid and tightly coordinated changes in a molecular process known to help regulate gene activity, a new study shows.
Dramatic changes in DNA methylation, a process that usually quashes activity of nearby genes, occur during the first six months of brain development, researchers report February 3 in Genome Research. Geneticist Jonathan Mill of the University of Exeter in England and colleagues made the discovery by examining the brains of 179 fetuses. Mill and colleagues strongly suspect that the DNA methylation changes they observed alter gene activity.
Some early DNA methylation changes could be early indicators of brain disorders such as autism, schizophrenia and Alzheimer’s disease, which appear long after birth, says Rena Li, a neurobiologist at the Roskamp Institute in Sarasota, Fla., who was not involved in the research.
DNA methylation is a process in which a methyl group — a carbon atom attached to three hydrogens — is attached to the DNA building block cytosine. When this type of chemical tag happens near a gene, it usually reduces that gene’s activity, but doesn’t alter the gene itself.
Mill and colleagues surveyed methylation at more than 400,000 spots in the genome. Over 28,000 spots either gain or lose methylation as the brain develops between day 23 and day 184 after conception, the researchers found.
Some genes undergo steady changes in DNA methylation levels; others experience periods of dramatic drops or rises. “An amazing thing is how quickly these things are occurring,” Mill says. The researchers could track some changes that happened within a day.
DNA methylation levels differed between male and female fetuses at more than 8,000 spots. Most of those — 7,538 — were on the X chromosome. The researchers expected those differences because in females, one X chromosome is shut down and becomes heavily methylated. But an additional 521 spots differed between male and female fetal brains on other chromosomes. Of those, 119 had previously been found to differ between male and female adult brains, indicating that those differences may be lifelong.
Other differences were not so stable. During the course of development, DNA methylation levels at 61 spots rose or fell differently in female brains than they did in male brains. In one case, a gene called RBPJ, male and female fetuses started out with the same levels of methylation. But at about day 100 after conception, the female fetuses started losing methylation of the gene, which is known to be involved in nerve cell development. It’s not clear, though, what the methylation change may do. In other cases, male and female brains start out differently but ultimately arrive at about the same level of methylation.
Sex differences in DNA methylation may influence brain structure and perhaps are involved in risk discrepancies between males and females for behavioral and brain disorders, says Andrew Jaffe, a computational biologist at the Lieber Institute for Brain Development and the Johns Hopkins Bloomberg School of Public Health. For instance, autism is five times as common in boys as in girls. Learning about DNA methylation and gene activity differences in development may help scientists discover why the disorder strikes boys more often. Mill and his colleagues found only one known autism-related gene, SHANK1, in which DNA methylation levels differed between male and female developing brains.
