Mapping the developing mind

Using advanced DNA sequencing technologies, researchers have produced a comprehensive map of DNA methylation and its dynamics in the brain throughout the life span of humans.

The research, conducted by Australian and US scientists, reveals that as the neural circuits of the brain mature, a large-scale reconfiguration of the neural epigenome also occurs.

“These new insights will provide the foundation for investigating the role the epigenome plays in learning, memory formation, brain structure and mental illness,” said Professor Ryan Lister, a genome biologist in the ARC Centre for Excellence in Plant Energy Biology at the University of Western Australia (UWA).

The ‘epigenome’ can be thought of as an additional layer of information on top of genes that changes the way they function. One component of the epigenome is DNA methylation. DNA methylation of C nucleotides, for example, can cause a nearby gene to be turned off.

DNA methylation in humans was thought to occur almost exclusively at C nucleotides followed by a G in the genome sequence - so-called ‘CG methylation’. However, in a surprise discovery in 2009, the researchers found that ‘non-CG methylation’ constituted a large fraction of DNA methylation in the human embryonic stem cell genome.

The researchers had previously observed both forms of DNA methylation in plant genomes when conducting earlier research that pioneered many of the techniques required for this brain study.

“Because of our earlier plant epigenome research we approached our human investigations from a distinct angle,” Professor Lister said. "We were actively looking for these non-CG methylation sites that were not widely thought to exist. Our new study adds to this picture by showing that abundant non-CG methylation also exists in the human brain.”

Non-CG methylation is almost exclusively found in neurons, and in patterns that are very similar between individuals.

“Surprisingly, we discovered that a unique type of DNA methylation emerges precisely when the neurons in a child’s developing brain are forming new connections with each other; essentially when critical brain circuitry is being formed.” said Eran Mukamel from the Salk Institute’s Computational Neurobiology Laboratory, a co-author of the study.

This finding is very important, as previous studies have suggested that DNA methylation may play an important role in learning, memory formation, and flexibility of human brain circuitry.

The researchers also found that patterns of methylation are dynamic during brain development, in particular for non-CG methylation during early childhood and adolescence.

Recent studies have suggested that DNA methylation may be involved in mental illnesses, including bipolar disorder, depression and schizophrenia.

Environmental or experience-dependent alteration of patterns of DNA methylation in neurons could lead to changes in gene expression, which change the way in which networks are formed. The researchers speculate that this, in turn, could lead to the appearance of mental disorders later in life.

This study is the culmination of more than two years’ hard work from an international, interdisciplinary team involving The Salk Institute for Biological Studies in La Jolla, California, UWA and several other international institutes.

Professor Lister and colleagues are now focussing their new research at UWA on how to control these epigenetic patterns within plant and animal genomes, which they hope will translate into breakthrough applications of benefit to human health and agriculture.

This article was published in Science.