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Comprehensive mapping of the human brain epigenome by UWA and US scientists uncovers large-scale changes that take place during the formation of brain circuitry.

Ground-breaking research by scientists from The University of Western Australia and the US, published this week in Science, has provided an unprecedented view of the epigenome during brain development.

High-resolution mapping of the epigenome has discovered unique patterns that emerge during the generation of brain circuitry in childhood.

While the ‘genome' can be thought of as the instruction manual that contains the blueprints (genes) for all of the components of our cells and our body, the ‘epigenome' can be thought of as an additional layer of information on top of our genes that change the way they are used.

"These new insights will provide the foundation for investigating the role the epigenome plays in learning, memory formation, brain structure and mental illness," says UWA Professor Ryan Lister, a genome biologist in the ARC Centre for Excellence in Plant Energy Biology, and a corresponding author in this new study.

Joseph R. Ecker, senior author of this study, and professor and director of the Genomic Analysis Laboratory at California's Salk Institute for Biological Studies in California, said the research shows that the period during which the neural circuits of the brain mature is accompanied by a parallel process of large-scale reconfiguration of the neural epigenome.

A healthy brain is the product of a long period of developmental processes, Professor Ecker said. These periods of development forge complex structures and connections within our brains. The front part of our brain, called the frontal cortex, is critical for our abilities to think, decide and act.

The frontal cortex is made up of distinct types of cells, such as neurons and glia, which each perform very different functions. However, we know that these distinct types of cells in the brain all contain the same genome sequence; the A, C, G and T ‘letters' of the DNA code that provides the instructions to build the cell; so how can they each have such different identities?

The answer lies in a secondary layer of information that is written on top of the DNA of the genome, referred to as the ‘epigenome'. One component of the epigenome, called DNA methylation, consists of small chemical tags that are placed upon some of the C letters in the genome. These tags alert the cell to treat the tagged DNA differently and change the way it is read, for example causing a nearby gene to be turned off. DNA methylation plays an essential role in our development and in our bodies's ability to make and distinguish different cell types.

To better understand the role of the epigenome in brain development, the scientists used advanced DNA sequencing technologies to produce comprehensive maps of precisely which C's in the genome have these chemical tags, in brains from infants through to adults. The study delivers the first comprehensive maps of DNA methylation and its dynamics in the brain throughout the lifespan of both humans and mice.

"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." says co-first author Eran Mukamel from Salk's Computational Neurobiology Laboratory.

Conventionally, DNA methylation in humans had been thought to occur almost exclusively at C's that are followed by a G in the genome sequence, so-called ‘CG methylation'. However, in a surprise discovery in 2009, the researchers found that a distinct form of DNA methylation, called ‘non-CG methylation' constitutes 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."

Surprisingly, this unique form of DNA methylation is almost exclusively found in neurons, and in patterns that are very similar between individuals. "Our research shows that a highly-ordered system of DNA tagging operates in our brain cells and that this system is unique to the brain," says co-author Dr Julian Tonti-Filippini, a computational biologist of the ARC Centre for Excellence in Plant Energy Biology and the WA Centre of Excellence for Computational Systems Biology.

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

"We found that patterns of methylation are dynamic during brain development, in particular for non-CG methylation during early childhood and adolescence, which changes the way that we think about normal brain function and dysfunction." says study co-author Terrence J. Sejnowski, head of Salk's Computational Neurobiology Laboratory. 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 these unique patterns of DNA methylation in neurons could lead to changes gene expression, adds co-corresponding author M. Margarita Behrens, a scientist in Salk's Computational Neurobiology Laboratory, "the alterations of these methylation patterns will change the way in which networks are formed, which could, in turn, 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 science superstars from The Salk Institute for Biological Studies in La Jolla, California, UWA and several other institutes internationally.

Professor Lister and Dr Tonti-Filippini 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 benefitting both human health and agriculture.

The work was supported by the Australian Research Council, the Western Australian State Government, the National Institute of Mental Health, the Howard Hughes Medical Institute, the Gordon and Betty Moore Foundation, the California Institute for Regenerative Medicine, the Leukemia and Lymphoma Society, and the Centre for Theoretical Biological Physics at the University of California, San Diego.

For more information:
Science Title: Global epigenomic reconfiguration during mammalian brain development Authors: Lister, et al, 2013. URL: TBD

Media references

Professor Ryan Lister (UWA Lister Lab)  (+61 8)  6488 4407  /  (+61 4) 48 375 394
Alice Trend (UWA ARC Centre for Excellence)  (+61 8)  6488 4481
Michael Sinclair-Jones (UWA Public Affairs)  (+61 8)  6488 3229  /  (+61 4) 00 700 783