For the first time, by mapping the epigenome of the human brain, scientists have revealed some large-scale changes that take place in human brain circuits from birth to adulthood.

The international team, including members from the University of Western Australia (UWA), The Salk Institute for Biological Studies in California, US, and Institut d’Investigació Biomèdica de Bellvitge (IDIBELL) in Spain, write about their findings in a paper published online in Science on 4 July.

Ryan Lister, a UWA professor and genome biologist, says in a statement:

“These new insights will provide the foundation for investigating the role the epigenome plays in learning, memory formation, brain structure and mental illness.”

While the genome can be thought of as an instruction manual, containing blueprints (the genes) for the biological components that make our bodies, the more recently discovered epigenome can be thought of as another layer of instructions about how to read the manual.

The epigenome is a record of the chemical changes that occur to DNA as the organism develops. Continuing with the instruction manual analogy, it is like a set of notes and bookmarks that say, ignore page 6, or do page 4 first.

Understanding the epigenome is key to understanding how genes affect health and disease under the influence of factors like lifestyle, diet and environment.

Now this new study offers an unprecedented view of the epigenome during brain development.

Using high-resolution mapping, the team has uncovered unique patterns in the epigenome that emerge as brain circuits develop during childhood.

Senior author Joseph R. Ecker, professor and director of the Genomic Analysis Laboratory at California’s Salk Institute for Biological Studies in California, says their study reveals the large-scale reconfiguration that the epigenome undergoes as brain circuits mature.

During healthy brain development, a number of processes take time to forge complex structures and connections among brain circuits.

For instance, the frontal cortex, which sits at the front of the brain, is critical for thinking, problem solving, making decisions, and acting on them.

The two main types of cell of the frontal cortex, the neurons and glia, do quite different things, yet they have the same genome pattern of DNA code, made from the letters A, C, G, and T. The difference in the way they behave is down to the epigenome.

One way the epigenome controls the interpretation of the genome is to tag the C letters in the DNA code. This is done using a chemical process called DNA methylation.

A tag causes that part of the DNA to be read differently to when it doesn’t have a tag: for example, it could silence a nearby gene, so it doesn’t code for a particular protein. In this way, the epigenome influences our bodies’ development and ability to make and differentiate among cell types.

For the study, the team used advanced DNA sequencing to find exactly where all the tagged Cs were in the brains of mice and people from baby stage to grown adults.

Co-first author Eran Mukamel, from Salk’s Computational Neurobiology Laboratory, says:

“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.”

At first, scientists thought that C-tagging only occured when a C was followed by a G (known as “CG-methylation”). Then later, they discovered non-CG methylation occurs a lot in the human embryonic stem cell genome.

The team had also seen both types of DNA methylation in plants, and because of this experience they approached this latest study from a slightly different angle:

“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,” says Lister.

They were surprised to find that this unique type of genome tagging happens almost only in neurons, and the patterns are quite similar from person to person.

“During this period [fetus to early adulthood], highly conserved non-CG methylation (mCH) accumulates in neurons, but not glia, to become the dominant form of methylation in the human neuronal genome,” write the authors.

Thus they have discovered the epigenome tags the genome in brain cells in a unique way, that is different to cells in the rest of the body.

The finding is important because previous research suggests this type of tagging is important for learning, how memory forms, and brain plasticity, or the flexibility of our brain circuits.

Ecker adds:

“These results extended our knowledge of the unique role of DNA methylation in brain development and function. They offer a new framework for testing the role of the epigenome in healthy function and in pathological disruptions of neural circuits.”

Ecker, Lister and colleagues were the first to map the whole human epigenome.

Written by Catharine Paddock PhD