Epigenetic MRI: A new DNA methylation imaging method

In the fields of psychiatry and neurology, brain imaging methods include a series of techniques that aim to measure the functioning of the brain, such as MRI, fMRI, MRS, PET, qEEG.

In the field of psychiatry, it is of critical importance in respect of researching the biological representations of disorders. For instance, major depression disorder has biological and electrophysiological markers. On this subject, you are welcome to take a look at the article series titled “Biomarkers in Major Depressive Disorder – 1, 2, 3”

The aforementioned method is used to obtain information regarding the functioning of the brain, based on the activities of the nerve cells in the brain. The nerve cell activities are quite short-term activities that take milliseconds. On the other hand, gene expression is a much slower activity that takes place within days, and it can offer information concerning the developmental state of the mind. For instance, while learning a new information creates changes in the nerve cells (synaptic plasticity), keeping the information in the memory for long period of time is made possible through DNA methylation and gene expression that take place in the nucleus of the nerve cell. Therefore, methods that are capable of imaging the gene expression on the brain may make great contributions to the clarification of matters, such as permanent learning, memory, mental aging, neurological disorders.

Scientists, and engineers working on the biomedical field are making use of animal models to implement various methods that could reveal the gene expression in the brain. These methods cannot be implemented on humans as they are mainly of invasive nature. Noninvasive attempts made through optical techniques like fMRI and PET, on the other hand, are limited to only a few genes, failing to provide comprehensive information regarding the human gene expression. Nevertheless, a new technique (2021) implemented on newborn pigs by the University of Illinois Urbana-Champaign suggests that it is possible to display the DNA methylation in the brain.

The authors of the study call this new technique “epigenetic MRI (eMRI)” This method fundamentally involves the labeling of the molecule on the DNA helix by passing through the blood-brain barriers in newborn pigs being nourished with foods enriched with a special amino acid (¹³C-Met), which is followed by the same being scanned by means of Carbon-13 nuclear resonance (¹³C NMR) and magnetic resonance spectroscopy (MRS).

Figure 1a – Enrichment of the food of newborn pigs with the methyl-¹³C amino acid. b – Labeling of the Methyl-¹³C molecule on the DNA helix by passing through the brain barrier. c – Determination of the rate of DNA labeled on a single hemisphere of the brain by means of c-¹³CNMR in a noninvasive manner, and determination of the same rate via invasive methods with the DNA tissue sample on the other hemisphere.

The subjects are divided into four groups as the experimental group and control group based on both the day of nourishment (10 days – 32 days) and the contents of nutrition (enriched with ¹³C-met – normal food). At the end of the experiment, a comparison is made regarding the percentage increase in the proportion of the DNA molecule (¹³C-5mdC) labeled in the brain to the total DNA molecule. Thus, the amount of labeling is determined. The results are as follows:

1. The rate of the labeled DNA in pigs nourished for 10 days with food enriched with ¹³C-Met, showed an increase by 3-4% compared to the control group.
2. This rate is over 12% in the experiment group nourished for 32 days.
3. The rate of increase in the experiment group nourished for 32 days is twice the rate in the group nourished for 10 days.
4. The increase in the labeled DNA rate is observed in all 8 brain regions analyzed (frontal cortex, thalamus, striatum, hippocampus, perirhinal cortex, midbrain, cerebellum, brain stem).
5. In the experimental group, however, the proportion of the labeled DNA molecule to the total DNA molecule remains the same.
6. The labeling is confirmed by the DNA analysis in the brain tissue samples, which is a noninvasive method.

The researchers claim that the labeled DNA rate of the experiment group within 10-32 days is so great as not to be associated with the increase of the brain volume, and that this increase is age-related or stems from DNA methylation, which is a result of cognitive processes like learning or memory creation. On the other hand, they also state that the epigenetic MRI method has certain advantages and disadvantages, as in all imaging techniques:

Advantages of the Epigenetic MRI method

• The fact that both the DNA labeling method (foods enriched with ¹³C-Met) and the imaging method (13C NMR and MRS) are noninvasive and applicable on humans.
• The fact that it can carry out an in vivo measurement of the DNA methylation which regulates the gene expression.
• The fact that it can provide information about a general gene activity in the brain.

Possible disadvantages of the Epigenetic MRI

• The carbon-13 nuclear magnetic resonance imaging method is a technique with low accuracy. Nonetheless, the study attempted to eliminate this problem by utilizing a fine labeling method, a high-technology imaging device, and advanced signal processing methods.
• ¹³C-Met can also be included in RNA and other protein methylations, in addition to the DNA methylation. The researchers report that this change in RNA occurred faster compared to DNA, and that its rate of incidence is proportionally much lower, though many further studies are required in this field.

Finally, the researchers state that this technique may offer information about a common activity just like other imaging techniques, and they emphasize that further studies must analyze the correlation between the neural activity, which is measured through the qEEG and fMRI methods, and the DNA methylation and gene expression measured via eMRI.

REFERENCES:
– Lam F, Chu J, Choi JS … and Li KC (2021-preprint). Epigenetic MRI: Noninvasive Imaging of DNA Methylation in the Brain. Doi: 10.1101/2021.08.20.457113