Methyl Donors and Epigenetics: The Story of the Famous Agouti Mice

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The Story of Sunny And Rusty- Two Mice Carrying the Agouti Gene

Once upon a time, in the heart of a bustling laboratory at Duke University in Durham, North Carolina, two cousin mice named Sunny and Rusty came into the world. They had the same dad and were born to identical twin sisters, Daisy and Rose, on the very same day. Despite having almost identical DNA that included the Agouti gene that leads to yellow fur, Sunny and Rusty’s lives took very different paths. This is their story, a tale from the perspective of two cousin mice destined for fame in the world of epigenetics.

Image Credit: Randy Jirtle and Dana Dolinoy, CC BY 3.0

Our lives began inside our moms, Daisy and Rose. Though our moms were identical in every way, the food they ate while they were pregnant with us was far from the same. Daisy, Sunny’s mom, was given regular mouse food. But Rose, my mom, was given a special diet rich in peculiar substances like folic acid and vitamin B12, known as methyl donors.

From the moment we were born, Sunny and I looked very different. Sunny was round and chubby, with a coat as radiant as a morning sunbeam. I, Rusty, on the other hand, was slim and sleek, with a coat as brown as a ripened chestnut.

As we grew older, we began to realize that our differences were more than fur-deep. Sunny had a harder time running and playing than I did. He would pant heavily after only a few minutes on the wheel, while I could run for what seemed like forever, enjoying the wind whooshing past my fur.

We soon understood that our lives were part of an extraordinary experiment, one that extended beyond our little world of cages and running wheels. The white-coated beings were keenly interested in us, always watching, always scribbling in their notebooks.

One day, I overheard them talking. They spoke of something called “epigenetics,” and how the food our mothers ate when they were pregnant with us influenced the way our genes worked. I learned that my mother’s special diet had ‘turned off’ a gene called the Agouti gene in me, resulting in my brown fur and healthier body. Sunny, whose mother had eaten normal mouse food, had the same gene ‘turned on,’ leading to his yellow coat and struggles with running and playing.

Our story spread far and wide, from one white coat to another, highlighting the profound impact of diet and environment on gene expression. We were living proof that our lives, our health, our very identities could be influenced by the world around us before we were even born.

While Sunny and I led different lives due to these unseen changes, we both played a critical part in the grand story of scientific discovery. Our small lives demonstrated that it isn’t just the genes you’re born with that matter, but how these genes are influenced by the environment.

As we squeaked and scampered around our cages, living our separate lives, we were united in our purpose. We showed the world that genes aren’t everything and that the choices made by those around us can significantly shape our lives. Despite our differences, we were proud, knowing that we were contributing to a better understanding of the fantastic, intricate dance between nature and nurture.

–Sunny & Rusty-The Most Famous of The Agouti Mice

How Methylation Turns Off Gene Expression

Every cell in the body has the exact same DNA, so how does a heart cell know how to be a heart cell rather than acting like a liver cell? Epigenetics.

Imagine your DNA as a long, winding road. This road has many stops along the way, which are like your genes. Now, picture a little car driving along this road, reading the signs at each stop. This car is like the machinery in your cells that reads your genes and uses their information to build stuff, like proteins.

Now, let’s talk about these things called ‘methylators.’ They’re like roadblocks. When a methylator adds a ‘methyl group’ (which is just a tiny molecule) onto a stop (a gene), it’s like putting up a barrier on the road. When our little car comes along, it can’t read the sign at that stop because the roadblock is in the way. This means the gene is effectively ‘turned off’ because its information can’t be read and used.

So, in simple terms, methylators work by sticking little molecules onto your genes that prevent your cells from reading and using the information at those genes. This process doesn’t change the genes themselves; it just controls whether or not they can be used. And that’s a big part of how each cell controls what our genes are doing at any given time.

What Happens If You Are Undermethylated?

When a cell experiences undermethylation, it means that there aren’t enough “roadblocks” or “methyl groups” being added to the DNA. Without these roadblocks, the cell’s machinery can read more of the stops along the DNA road – or in other words, more genes can be active. When more genes are turned on than usual, it can result in an overproduction of certain proteins or other gene products. This can disrupt the normal balance of activities within the cell and lead to a variety of issues. For example, undermethylation has been linked to some types of cancer and mental health conditions, as the overactivity of certain genes can promote uncontrolled cell growth or affect brain chemistry.

What Happens If You Are Overmethylated?

Overmethylation, or hypermethylation, in a cell means that there are too many “roadblocks” or “methyl groups” being added to the DNA. When this happens, it’s like having too many stops blocked off along the DNA road. This means that a lot of genes that should be active are effectively turned off because their instructions can’t be read by the cell’s machinery.

This can cause problems because certain important proteins and other gene products might not be produced in the right amounts, disrupting the normal balance of activities within the cell. For instance, overmethylation of certain genes has been associated with some types of cancer, because the genes that normally help keep cell growth in check are turned off, allowing cells to grow and divide out of control.

In terms of mental health, overmethylation can also have an impact. For example, it’s been linked to conditions such as anxiety and depression, possibly due to the reduced activity of genes involved in regulating our mood and responses to stress.

So, in short, if you’re overmethylated, it means too many of your genes are being silenced, which can interfere with normal cell function and possibly lead to various health issues.

How Do You Find Out Your Methylation Status?

Determining a person’s methylation status typically involves a series of lab tests. One common method is through blood tests, specifically looking at levels of certain substances that are associated with methylation processes in the body. Various lab tests for methylation status are available through the NutriScape Lab Shop (Affiliate link). These include:

  • Homocysteine (Affiliate Link): High levels of homocysteine in the blood can suggest issues with methylation, as homocysteine is converted into methionine (a crucial amino acid for methylation) in a process that requires methyl groups. If methylation isn’t happening as it should be, homocysteine levels can increase.
  • MTHFR Genetic Test (Affiliate Link): The MTHFR test determines if you have a genetic variation that affects your ability to process folate to its active form. Genetic variants in the MTHFR gene may put you at an increased risk for cardiovascular disease. The MTHFR Genetic Test (affiliate link) is available through the NutriScape Lab Shop. View a Sample Report.
  • Methylation Profile (Affiliate Link): The Methylation Profile looks at the levels of methionine, cysteine, SAM, SAH, homocysteine, cystathionine, and the ratio of SAM to SAH (the methylation index) to assess your body’s metabolism of methionine. This Methylation Profile Lab (affiliate link) is available through the NutriScape Lab Shop. View a Sample Report.

Comprehensive Nutrition Labs

There is also the option of going with more comprehensive nutritional testing. These are often not covered by health insurance but can be covered by health savings accounts.

  • NutrEval FMV (Affiliate Link): Comprehensive Nutrient Metabolism Testing gives exquisite insight into your nutritional status, oxidative stress, and detoxification ability. An excellent report is generated to guide your treatment of any concerns brought out by the test.
  • Metabolomix+ (Affiliate Link): Metabolomix+ focuses on core areas of metabolism and provides an overview of amino acids, fatty acids, oxidative stress, and more. It uses a urine sample. An excellent report is provided to guide your response to the results the test provides. Note that the Omega 3 evaluation shown in the sample report is not a part of this test, but is available in the NutrEval FMV.

It’s important to note that while these tests can give some indication of a person’s methylation status, they can’t provide a complete picture on their own. They need to be interpreted in context with a person’s overall health, symptoms, and medical history.

What Supplements Are Methyl Donors?

Although there are a number of other nutrients that are involved in methylation pathways, the list of supplements that directly supplies methyl groups is limited to these four:

What Your Methylation Status Means for Your Supplement Choices

Keep in mind, while supplements can support balanced methylation, they aren’t a one-size-fits-all solution. Each person’s needs are unique, and factors such as other health conditions, genetic factors, and overall diet can all influence what kind of supplementation would be most beneficial. So, it’s crucial to work with a healthcare provider or a Registered Dietitian Nutritionist to determine the best approach to supporting your body’s methylation processes.

How to Supplement When You Are Undermethylated

If your lab tests suggest that you’re undermethylated, you may benefit from an increase in nutrients that donate methyl groups, or “methyl donors”. Some supplements that provide these essential methyl donors include:

  • Folate (Vitamin B9): This is a key methyl donor. However, some people have a genetic variant (such as the MTHFR mutation) that makes it hard for them to convert the usual supplemental form of folate (folic acid) into the form the body can use. In such cases, a form called L-methylfolate may be recommended.
  • Vitamin B12(Methyl Cobalamin): This vitamin works closely with folate in the methylation process. It’s often included in B-complex supplements or can be taken on its own.
  • SAMe (S-Adenosyl methionine): This is a molecule that donates methyl groups in various reactions in the body, including DNA methylation.
  • Betaine (also known as trimethylglycine): This nutrient donates methyl groups and is often used in supplements for supporting methylation.
  • Methionine: This is an amino acid that the body can use to make SAMe, so it’s also a kind of indirect methyl donor.

What Supplements Should You Take If Tests Show That You Are Over-methylated?

Overmethylation can happen for several reasons. Certain genetic variations can also make your body more efficient at methylation, leading to over-methylation. Another reason people become over-methylated is by taking too many methyl donor nutrients through supplements.

What To Avoid:

If you’re identified as over-methylated, it’s generally recommended to avoid supplements that are high in methyl donors, especially the methylated forms of certain vitamins. This includes:

  • SAMe (S-adenosylmethionine)
  • Betaine (Trimethylglycine)
  • Folate/Vitamin B9 (Methylfolate)
  • Vitamin B12 (Methyl Cobalamin)

What To Take

Instead of these, consider supplements that can help balance methylation processes and support overall metabolic health. These might include:

  • Magnesium: This mineral supports numerous reactions in the body, including some that involve methylation. It doesn’t provide methyl groups itself, but it can support overall metabolic health.
  • Vitamin B6: Although it plays a role in methylation, it’s also involved in a wide range of other reactions in the body and might help balance methylation processes.
  • Niacin (Vitamin B3): This vitamin can help to use up excess methyl groups and has been suggested to be beneficial for some people who are over-methylated.

How Methylation Nutrients Matter In Pregnancy

Methylation is an essential process that happens at the cellular level in our bodies. During methylation, a methyl group (consisting of one carbon and three hydrogen atoms) is added to DNA molecules, influencing their activity but not their structure. This process plays a crucial role in regulating gene expression and protein function.

Undermethylation, or hypomethylation, during pregnancy could have several potential implications for offspring, based on both theoretical considerations and research findings.

  • Neurodevelopmental disorders: There is some evidence suggesting that undermethylation could potentially contribute to neurodevelopmental disorders in offspring. For example, some studies have found associations between certain genetic variations that affect methylation and an increased risk of conditions like autism [PMC8813730] and ADHD, although the exact nature of these relationships is still being investigated.
  • Impaired fetal growth and development: Undermethylation could theoretically lead to impaired fetal growth and development, as methylation plays a critical role in cell division and differentiation.
  • Increased risk of chronic conditions later in life: Epigenetic changes, such as those caused by undermethylation, could theoretically increase a child’s risk of developing chronic conditions later in life, like cardiovascular disease or certain types of cancer.

However, it’s important to note that while these are potential implications, the relationship between undermethylation and these outcomes is complex and can be influenced by many other factors, including other aspects of maternal health and genetics. Our understanding of these processes and their implications for health is still evolving. Therefore, pregnant women should consult with their healthcare provider about their methylation status and what it means for their pregnancy and their baby’s health.

Methylation in Childhood ADHD

A 2020 review of the studies found that differences in DNA methylation at birth are associated with symptoms of ADHD in children, suggesting that these differences could potentially serve as a marker for the disorder and may play a role in its development. [PMC7665047]

Effects of Stress and The Environment on Methylation

Environmental factors play a significant role in influencing methylation, an important epigenetic mechanism that helps control gene expression. These factors can shape methylation patterns, potentially affecting overall health.

Chronic physical and psychological stress, for instance, can alter methylation patterns. Such changes may specifically target genes that regulate our response to stress, potentially influencing mental health and susceptibility to certain diseases. Similarly, lifestyle factors like smoking and heavy alcohol consumption are known to cause changes in DNA methylation. Some studies suggest that the methylation changes caused by smoking may persist long after a person has quit, indicating the long-term impact smoking can have on our methylation patterns.

Air pollution is another environmental factor that can affect methylation. Exposure to particulates found in pollution has been linked to changes in methylation patterns. Such changes may increase the risk of respiratory and cardiovascular diseases. Additionally, exposure to certain chemicals and toxins, such as heavy metals like lead and arsenic, can influence DNA methylation. For example, prenatal exposure to high lead levels has been associated with methylation changes in children.

Interestingly, regular physical activity seems to have a beneficial effect on methylation patterns, particularly in genes related to muscle development and metabolism. And finally, age itself is associated with methylation changes over time, potentially impacting age-related diseases.

These factors interact in complex ways with each other and with our genetics to shape methylation patterns and, in turn, influence health. These relationships continue to be studied, and our understanding of these processes and their health implications is still growing.

To Sum It Up

Methylation plays an invaluable role in gene expression, cell differentiation, and many, many other aspects of our health. Its implications span from normal biological processes to complex diseases, accentuating its critical role in the framework of human biology. Understanding methylation patterns and their implications can pave the way for breakthroughs in personalized medicine, where tailoring treatments could potentially take into account an individual’s unique methylation landscape.

This Article is Not a Substitute for Medical Advice

Dietary supplements are not designed to diagnose, treat, cure, or prevent any disease. The Supplement Sciences website seeks to provide comprehensive access to the most relevant supplement information along with convenient online ordering. We do not provide medical advice and cannot guarantee that every product suggested is completely without risk. Since each person is unique in their health history and medication use, it is important to discuss supplements with your personal physician. Specifically, pregnant women and individuals being treated for cancer or liver or kidney problems must consult their physician about every nutritional supplement they plan to take. People taking medications for the treatment of HIV or with a history of organ transplant must not take supplements without consulting with their physician.

About the Author

Stephanie Figon, MS, RDN, LD

Creator of Supplement Sciences and NutriScape.NET. As a dietitian since 1992, Steph has had experiences in consulting, 15 years in clinical, and has operated a private practice nutrition counseling office for since 2011. Log in to comment and save this article on your board or send your comments to

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