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New MRI Method Images Epigenetic Changes in the Brain

New MRI Method Images Epigenetic Changes in the Brain

New MRI Method Images Epigenetic Changes in the Brain

New MRI Method Images Epigenetic Changes in the Brain

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A collaborative study from researchers at the University of Illinois (U of I) Urbana-Champaign has developed a new method that enables magnetic resonance imaging (MRI) to capture DNA methylation in piglet brains.

Gene expression changes in response to external stimuli

The genome – an organism’s entire DNA code – is often likened to a recipe book. The pages of this book represent different genes that, like a recipe, provide instructions for our cells to create proteins via the processes of transcription and translation. These proteins are the cellular “workhorses” that are involved in various molecular processes, ultimately shaping the cell’s unique function within the organism.

While every cell within an organism possesses the same genes, not every cell carries the same function, owing to the “turning off” and “turning on” of specific genes at different moments in time, known as gene expression. The expression of genes can be influenced by a variety of different factors, such as environmental exposures, disease and even trauma.

Epigenetics refers to the study of how cells regulate gene activity without causing changes to the DNA sequence itself. There are different types of epigenetic changes, including DNA methylation and histone modification.

What is DNA methylation?
DNA methylation is an important process in gene activity regulation. Methyl groups, which consist of one carbon and three hydrogen atoms) are attached to the DNA backbone. They are able to block the proteins that are required to “read” a gene for it to be transcribed into RNA and translated into protein. Thus, when the methyl group is attached, the protein is not produced. This is a reversible process. Removal of the methyl group – via demethylation – effectively turns the gene “on”.

The brain’s control systems

Epigenetics research is advancing our understanding of human biology. Studying gene expression in the brain, and how it changes throughout different experiences – like learning and memory – has been a large focus of neuroscience research over recent decades.

“There is an extensive literature from many laboratories, including some of ours, showing that there are changes in brain gene expression and epigenetic changes in the brain in response to a variety of experiences and exposures,” Professor Gene Robinson, director of the Carl R. Woese Institute for Genomic Biology at the U of I, told Technology Networks. Robinson’s previous research has demonstrated that specific genes within the brain are up- or down-regulated in organisms like the Western honeybee – Apis mellifera – when it undergoes environmental changes or stressors.

The brain, Robinson described, has two control systems: “A fast system based on changes in neuronal activity that occur on fast timescales, measured in milliseconds to minutes, and a slower system based on changes in gene activity that occur on slower timescales, measured in minutes to hours and even longer.” The former system, whereby there are fast-occurring changes in neuronal activity, may occur when an organism encounters a threat, for example. The neuronal synapses fire signals that trigger thoughts such as “run”, or “pull your hand away from that hot surface”.

But the gene expression changes occurring in the brain persist long after the threat is resolved. If you’ve ever encountered mindfulness, you might be familiar with the saying “neurons that fire together, wire together”. The notion being that, should you practise mindfulness frequently, you may be able to alter the structure of your own brain due to changes in gene expression, signalling molecules and new neuronal connections.

This flexibility of the brain is known as neuroplasticity. The control systems that Robinson refers to ultimately contribute to the building of the brain’s plasticity. It’s therefore clear how epigenetic changes, which regulate gene expression, are important for learning and memory.

A new non-invasive method to study gene expression

The difficulty in studying the molecular processes associated with the brain’s control systems is that an organism requires its brain to live. Consequently, the majority of research in this field has relied on post-mortem analysis of gene expression. Previous efforts to explore epigenetic mechanisms in the human brain in real-time relied on imaging a specific enzyme known to be involved in epigenetic mechanisms. Unfortunately, the method was not sufficiently targeted enough to yield novel insights.

Robinson and colleagues at the U of I wondered how they may be able to adopt MRI to further advance the study of neuronal gene expression in living organisms. “MRI has revolutionized neuroscience by providing a non-invasive method to measure and map rapid changes in neuronal activity,” he explained.

In a new multi-disciplinary study involving Robinson, led by Dr. King Li, a professor in the Carle Illinois College of Medicine at the U of I and bioengineering professor Dr. Fan Lam – amongst others – the scientists came up with a solution.

Li noted that the enzyme methionine can carry carbon-13 into the brain. Carbon-13 is a rare isotope of carbon that is often used in medical studies as a marker. This meant that, in the brain, methionine could potentially donate a carbon-13 labeled methyl group for DNA methylation to occur, which the researchers could then capture via MRI. They nicknamed their process “epigenetic MRI”, or “eMRI”.

However, MRI signals from carbon-13 are sometimes weak – a challenge that required collaboration to overcome. “Two members of our team, professors Liang and Lam, have extensive experience analyzing and enhancing a variety of signals related to nuclear magnetic resonance. They applied their expertise to this new problem and achieved impressive performance,” Robinson said.

Carbon-13 labeled methyl groups imaged in the piglet brain

Initially, the research team began their study by administering carbon-13-labeled methionine to rodents through their food supply before moving on to piglet models. They found that MRI could detect signals from carbon-13-labeled methyl groups in the brain, and that these signals increased when the piglets were imaged a few weeks after birth compared to when they were new-borns. This finding, Li said in a new release, is encouraging as it reflects the fact that the signal is environmentally responsive.

“It is known from animal studies that brain regions that are most involved in learning and memory experience more epigenetic changes. There also were regional differences in DNA methylation across the pig brain, just like there are regional differences in classical MRI studies,” Li added.

The proof-of-concept study provides a “real-time” method for exploring the brain’s control systems. As MRI is widely adopted in human medicine, the research team envision moving to human studies as the natural next step for advancing the method. “In addition to applications in neurology, we envision applications in the social sciences to help elucidate various forms of “biological embedding,” i.e., how aspects of the environment “get under the skin” to affect brain, behavior, and other aspects of biology. These could relate to socioeconomic factors and other important elements of the social environment,” Robinson said.

A current limitation highlighted by Robinson is the signal to noise ratio, which must be enhanced to reduce the scan time. Additionally, DNA methylation is only one form of epigenetic control, and thus, a better understanding of the connections between global DNA methylation changes and those that occur in the brain need to be better elucidated.

Should the method be further fine-tuned, Robinson expects that its applications extend beyond the study of one type of epigenetic change: “The general methods allow for other possibilities,” he concluded.

Reference: Lam F, Chu J, Choi JS et al. Epigenetic MRI: Noninvasive imaging of DNA methylation in the brain. PNAS. 2022. doi: 10.1073/pnas.2119891119.

Professor Gene Robinson was speaking to Molly Campbell, Senior Science Writer for Technology Networks.      

Meet the Author
Molly Campbell
Molly Campbell
Senior Science Writer