Computational Systems Biology News

Artwork: Scot Nicholls

SCIENTISTS EXPLORE THE MIND WITH EPIGENOMIC MAPS

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 today (July 4) 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.

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

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 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 scientists 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 Center for Theoretical Biological Physics at the University of California, San Diego.

UWA Media Release July 2013.

Congratulations for Conny Hooper at CBSM

Winner of the Human Genetics Society of Australasia Poster Prize

New Centre scientist Conny Hooper is only a recent convert to plant science.

In fact, just last week she took home the Human Genetics Society of Australasia poster prize at the Combined Biological Sciences Meeting for her PhD work profiling childhood brain tumours.

By comparing the transcript profiles (gene-products) from healthy and cancerous samples in the developing brain, Conny identified surprising "signatures" representing different stages of brain development. The differences between healthy cells and brain tumour cells suggested that the cell types originated from distinct areas and time periods in the brain. She also found several genes that may have contributed to the cancer development and may be useful as clinical markers.

These fantastic results were described in her poster "Developmental-Intersect-Analysis using human Neural Stem and Precursor Cells identifies Candidate Genes involved in Childhood Medulloblastoma Pathogenesis".

Computational biology is a powerful and relatively new tool that is applicable across all fields of biology. We are delighted to welcome Dr Hooper into our ranks to help us uncover how plant genes and their products are matched to overall plant performance and yield.


Western Australia's Mysterious Underground Orchid Revealed

Rhizanthella gardneri is a cute, quirky and critically endangered orchid that lives all its life underground. It even blooms underground, making it virtually unique amongst plants. Last year, using radioactive tracers, scientists at The University of Western Australia showed that the orchid gets all its nutrients by parasitising fungi associated with the roots of broom bush, a woody shrub of the WA outback. Now, with less than 50 individuals left in the wild, Plant Energy Biology scientists have made a timely and remarkable discovery about its genome.

Read our story in Cosmos magazine
Link to the UWA media release

Publication:

Delannoy E, Fujii S, Colas des Francs C, Brundrett M and Small ID (2011) "Rampant Gene Loss in the Underground Orchid Rhizanthella gardneri Highlights Evolutionary Constraints on Plastid Genomes" Molecular Biology and Evolution (in press) online

Sota Fujii Awarded:

Plant Energy Biology Research Associate Dr Sota Fujii is off to a terrific start in 2011. Following on from his recent publication (Full Text) in the Proceedings of the National Academy of Sciences (PNAS), he has won both a Japanese research award and a fellowship to continue his valuable work in plant genetics.

Dr Fujii was selected from 300 agricultural scientists for the position of "Super Postdoctoral Fellow" by the Japan Society for the Promotion of Science (JSPS). The fellowship is funded by the Japanese Ministry of Education, Science, Sports and Culture.

I will do my best to use this precious money from Japanese Taxpayers to contribute to the advancement of life science at global level, like my hero Dr. Barbara McClintock,

pledged Dr Fujii.

Dr Fujii's research on restorer to fertility genes in plants has also earned him a Inoue Research Award for Young Scientists. This prize for early career scientists highlights the great work being done by this promising young researcher.


Centre contributes to the second most important scientific discovery of 2009

From the original Time article by EBEN HARRELL

The Top 10 of Everything for 2009

2. The Human Epigenome, Decoded

DNA

The decoding of the human genome nearly a decade ago fueled expectations that an understanding of all human hereditary influences was within sight. But the connections between genes and, say, disease turned out to be far more complicated than imagined. What has since emerged is a new frontier in the study of genetic signaling known as epigenetics, which holds that the behavior of genes can be modified by environmental influences and that those changes can be passed down through generations. So people who smoke cigarettes in their youth, for example, sustain certain epigenetic changes, which may then increase the risk that their children's children will reach puberty early. In October, a team led by Joseph Ecker at the Salk Institute in La Jolla, Calif., studied human skin and stem cells to produce the first detailed map of the human epigenome. By comparing this with the epigenomes of diseased cells, scientists will be able to work out how glitches in the epigenome may lead to cancers and other diseases. The study, which was published in the journal Nature, is a giant leap in geneticists' quest to better understand the strange witches' brew of nature and nurture that makes us who we are.


Breaking News!

October 2009: After working on the Arabidopsis methylome Ryan Lister, Julian Tonti-Filippini and Harvey Millar have co-authored a Nature Paper about the the human methylome!
Read More...

An overview for the general reader can be found at the Economist

Centre researchers part of US consortium that has mapped the human epigenome — the genome's new clothes

A major breakthrough study, published today in Nature, has provided a complete roadmap of the human epigenome and has major implications in the treatment of human diseases and for the development of stem-cell based regenerative medicine. An epigenome may be thought of as the clothes that dress a genome, controlling the way genes are packaged and expressed without actually altering the underlying DNA code. Epigenomes are flexible and can be changed by environmental factors such as diet, stress and chemical exposure, leading to changes in gene expression. These changes can be temporary or they can be more permanent, with some studies suggesting they can be passed down from generation to generation.


This research was conducted by an international consortium of The Salk Institute for Biological Studies; Ludwig Institute for Cancer Research and University of California San Diego; Morgridge Institute for Research, the Genome Centre for Wisconsin and The University of Wisconsin-Madison; and The University of Western Australia. It is part of, and funded by, the NIH Roadmap Reference Epigenome Consortium. The consortium including three researchers linked to the ARC Centre of Excellence in Plant Energy Biology and WA Government-funded State Centre of Excellence in Computational Systems Biology.

Julian and Harvey
Chief Investigator Dr Harvey Millar and PhD candidate Julian Tonti-Filippini with Julian's Genome browser in the background. [click to expand image]

This is the first study to fully sequence the human epigenome at single-base resolution, and required re-sequencing the human genome more than thirty times to map the location of tens of millions of tiny biological markers known as cytosine methylation sites.

The paper also reveals a remarkable difference between normal human cells and stem cells in the type and pattern of methylation sites. The stem cells contain many methylations at unusual sites in the genome that must be actively propagated from one cell division to another. This finding could provide the key to understanding how stem cells can make many different cell types, while other human cells have defined roles that cannot be changed.

The lead researcher in this groundbreaking study was Dr. Ryan Lister, a former Centre PhD student from Professor Jim Whelan's laboratory, who has been based at the Salk Institute for Biological Studies in San Diego, California for several years.

UWA PhD student Mr Julian Tonti-Filippini, supervised by UWA Professor Harvey Millar, collaborated with Dr Lister to develop software tools for data handling, analysis and visualisation. This is the second collaboration between the three scientists, following on from a successful study that mapped the complete epigenome of the model plant Arabidopsis thaliana, published last year in the journal Cell.

cell cover art

Julian Tonti-Filippini makes the cover of Cell

Centre researchers Julian Tonti-Filippini and Harvey Millar collaborated with researchers from the JR Ecker Laboratory at the Salk Institute in San Diego to analyse DNA methylation and the mRNA and smRNA components of the transcriptome by new deep sequencing technologies. Julian's AnnoJ Web 2.0 genome browser, developed in the centre, was a key tool in the visualisation of this huge dataset. This groundbreaking research was published April 17th in Cell and the data can be viewed via AnnoJ at Salk.



logos The Government of Western Australia The University of Western Australia Australian Research Council Centre of Excellence in Plant Energy Biology