FTO and m6A methylation: From COVID to Cancer to Obesity

Every second of everyday reactions are taking place inside your cells that turn the information in DNA into the proteins that run our lives. But have you ever wondered how cells can regulate which genes are translated and how much of a specific protein is created? It turns out that the FTO gene, which was originally discovered through obesity research and dubbed the ‘fatso’ gene, is just one player in a fascinating and complex process.

I’m going to dive into some recently discovered ways that your cells regulate and fine-tune exactly which proteins are created. It is a timely topic because this ties into how mRNA from a virus, such as COVID-19, is created. It is also a timeless topic… while the research is new, this method of controlling which proteins are created is ancient and used throughout the plant and animal kingdoms.

Regulating gene expression: FTO and mRNA methylation

I’m going to admit up-front here that this article gets a little more in-depth with the new research – a little more complicated – than most Genetic Lifehacks articles. If you are just looking for a quick overview of FTO and weight, jump over to this article.

First, a quick overview of some basic biology to make sure we are all on the same page. Then I’ll explain the recent research on mRNA m6A methylation.

What is mRNA?

I often state that a gene codes for a protein – and that is true in a general sense.

Genes are segments of DNA that are transcribed into mRNA (messenger RNA). Ribosomes then translate the mRNA into the amino acids that make up proteins.

Sounds pretty straightforward…but there is a lot more going on inside the cell.

Except for red blood cells, all the cells in your body have the same DNA, and the same genes. Nevertheless, not every gene produces a protein. For example, the cells in your liver both look and function way differently than your brain cells. In liver cells, different genes translate into proteins and enzymes.

Therefore, while your cells all have the same instructions for making proteins, not all genes will be transcribed and translated into proteins.

Epigenetics refers to the process by which genes turn ‘on or off’. Essentially, there are multiple ways of marking genes to be turned on for translation or to be turned off and not translated.

In addition to turning a gene ‘on’ or ‘off’ for transcription into mRNA, the translation from mRNA into the final protein is also something that can be regulated in a cell.

Once mRNA is created, it moves out of the cell nucleus and into the cytosol for translation into a protein by the ribosomes. Along the way, there are a bunch of ways that the mRNA can be modified so that it can’t complete the steps needed to be turned into a protein. It can also be modified to produce slightly different proteins or enzymes. Furthermore, there is a way to modify the mRNA so that it facilitates translation into proteins. (These mRNA modifications are known as the epitranscriptome.)

Adding a methyl marker to mRNA: writers

One of the most common ways that mRNA is altered is through methylation markers attaching at certain spots on the mRNA.

The most common spot on the mRNA is a certain adenosine molecule that a methyl group can be attached to. This is called N6-methyladenosine (m6A) modification.

Essentially, a methyl group (CH3) is added to the m6A spot on the mRNA.

Related article: Methylation cycle, methyl groups, and MTHFR

What does this methylation mark do?[ref]

• The m6A methylation can cause the mRNA for a protein to be unstable and then degraded.
• Or, it can cause it to remain in the nucleus and not move into the cytosol to become a protein at that particular time.
• And it can alter the way that the mRNA forms in the protein.
• Additionally, a methyl group in the right spot on the mRNA can increase stability and promote translation.

What causes m6A methylation?

M6A writers are different proteins (enzymes) that carry out this task. The two most common are METTL3 and METTL14. M6A writers are different proteins (enzymes) that carry out this task.

The METTL3 and METTL14 enzymes ‘write’ or attach the methyl group onto the mRNA at specific spots. The m6A writers, called RNA methyltransferases, are enzymes that transfer a methyl group to an RNA.[ref]

The METTL3 writer and m6A methylation are an essential part of embryonic development. Without METTL3, a fetus is not viable.[ref]

Enough with writers – let’s get on to the main topic, FTO:

Erasing the m6A markers: FTO

Just like some writers are adding the methyl groups, there are eraser proteins that can remove the m6A methylation. These ‘erasers’ are called m6A demethylases (enzymes that remove the methyl group from m6A).

In some situations, erasing the m6A methylation then allows the mRNA to become the protein. The eraser can ‘turn up the volume’ of the protein in this way. But in other situations, erasing the methyl group can alter the stability of the mRNA.

Researchers have found two main m6A erasers: ALKBH5 and FTO.

Researchers discovered that the FTO gene dubbed the ‘fatso gene’, strongly correlated with higher BMI and obesity in 2007.

More recently, researchers discovered that FTO is an m6A eraser that removes methyl groups from mRNA. This discovery has opened up huge avenues of research on topics from cancer to immune response to heart disease.

Reading the m6A markers:

There is one more player in the mRNA methylation game: the readers. These reader enzymes are responsible for degrading the methyl-marked mRNA so that it doesn’t complete the cycle of becoming a protein. The reader proteins include YTHDF2, YTHDF1, and IGF2BP.

One article sums up: “In short, writers and erasers work together to modulate m6A dynamics and maintain its homeostasis in cells, while the activity of readers allows m6A to exert its influence in each step of the RNA life cycle.”[ref]

Here is a visual overview of the different outcomes from m6A readers:[ref]

Recap: Genes are transcribed into mRNA. The mRNA can be translated into a protein, or it can be marked with methyl groups in a way that alters it (splices it, causes it to degrade, moves it to the cytosol, or stabilizes it for translation). FTO is an eraser of those marks.

What does the FTO gene impact?

The initial research on the FTO gene was all about how it relates to increased BMI and increased fat cell creation. It turns out obesity is just the very tip of the iceberg for what this gene influences.

Let’s dig into the latest research on FTO as an m6A eraser:

Cancer and FTO

Much of the current research on m6A methylation of mRNA focuses on cancer. In many types of cancer, dysregulation of m6A methylation promotes the growth and metastasis of cancer.

As an oversimplification, cancer mutations cause either too much cell growth or promote metastasis. The key is to prevent both.

Dysregulation can mean too much of a methylation writer on certain mRNA, too many or not enough methyl groups available, or too much of the eraser.[ref][ref]

Two ways that dysregulation of m6A methylation impacts cancer are:

• oncogenes can be activated to promote unchecked growth – or –
• tumor suppressor genes can be repressed via m6A methylation.

Here are a few of the recent discoveries related to FTO and cancer:

• In gastric cancer, higher levels of FTO are an independent risk factor for overall survival. FTO promotes metastasis by erasing m6A methylation marks on certain mRNAs (Integrin β1).[ref]
• FTO promotes tumor progression in esophageal squamous cell cancer and colon cancer.[ref]
• But it isn’t as simple as more FTO is bad and less is good. Another study on FTO in colon cancer showed that the hypoxia present in the tumor suppressed FTO, and the FTO could also exert a tumor-suppressive role by modifying certain mRNAs.[ref]
• The FTO genetic variants that increase FTO expression have links to a significant decrease in the risk of prostate cancer.[ref]
• A Japanese study shows that the FTO variants have associations with an increased relative risk of pancreatic cancer independent of obesity.[ref]
• Inhibiting FTO may be a new target for cancer therapy in leukemia.[ref]
• In contrast to other types of cancer, recent research points to FTO playing a preventative role in liver cancer.[ref]

The Circadian Clock is controlled by m6A methylation

Your body has a built-in circadian rhythm controlled by a molecular clock. The circadian rhythm controls when different activities happen in the body – the rhythm of hormones, body temperature, enzyme production, and even sleep.

The circadian ‘clock’ is a molecular one instead of a mechanical clock with gears. The rise and fall of core circadian proteins (CLOCK and BMAL1 vs. PER and CRY) control the circadian rhythm throughout the body.

Researchers recently discovered that m6A mRNA methylation plays a big role in the circadian clock.[ref]

Specifically, FTO is responsible for controlling the levels of the core circadian clock genes CLOCK and BMAL1. [ref] m6A methylation is also responsible for downstream lipid production in the liver via circadian regulation.[ref]

Neurogenesis

Adult neurogenesis refers to the continual (slow) replacement of neurons in the brain from neuronal stem cells.

Depending on your age, you may have learned, like I did, that you can’t make new brain cells. (Was this why your brain on drugs looks like a fried egg? perhaps I’m misremembering the commercials on that).

It turns out the ‘you can’t make new brain cells’ part of my high school textbook was wrong. Instead, there is lifelong neurogenesis in all mammals, including humans.[ref]

Recent research (2021) shows that FTO is important in adult neurogenesis as well as learning and memory.

Researchers found that reducing the FTO protein in the brains of animals caused impaired learning and memory.[ref]

Other research shows that FTO regulates the expression of BDNF, brain-derived neurotrophic factor, which is important in brain plasticity, cognitive function, mood disorders, and dementia.[ref]

It isn’t as simple as FTO is always “good” in the brain. Instead, FTO has many different effects and interacts with many other genes. Additionally, keep in mind that FTO is the eraser, so the m6A methylation marks (methyl groups) need to be added by the writer in the first place for FTO to matter.

The FTO variant that increases the amount of FTO correlates to an increased risk of Alzheimer’s only in APOE E4 carriers.[ref]

In Parkinson’s disease, an overall decrease in m6A methylation exists.[ref] Early animal research points to inhibiting FTO as having the potential to protect the dopamine neurons that are targeted in Parkinson’s.[ref]

A recent study found that children with the FTO variant linked to obesity also have greater brain volume in certain regions.[ref]

Heart disease and FTO

The genetic variants linked to increased FTO (listed below) are also linked to an increased risk of heart disease. This increase in risk is after the researchers adjusted for things like sex, age, and BMI. Thus, it is likely that being overweight wasn’t the (only) cause of the increase in heart disease risk. Instead, it was the increased FTO m6A eraser.[ref]

Viral RNA replication

Viruses hijack the host cell’s DNA and RNA replication pathways to replicate the virus.

RNA viruses, or at least some RNA viruses, incorporate the m6A methylation writers and erasers to modify both the viral RNA and to modify the host’s immune response. Also, m6A methylation impacts DNA viruses.[ref]

Another thing that m6A methylation does is help the innate immune system figure out viral RNA and human mRNA.

While m6A has been known since the 1970s, it was only a few years ago that technological breakthroughs allowed researchers to understand the role with viruses.

Keep in mind that this is all pretty new (all since 2016), and thus more research is needed here before applying this information…

Porcine endemic diarrhea virus (PEDV), an aptly named coronavirus, gives pigs deadly diarrhea. Researchers recently investigated the interaction between m6A methylation and PEDV replication. The results showed that silencing FTO decreased viral replication. The researchers also found that the virus caused alterations in the methylation of some of the host mRNA – specifically relevant to the viral diarrhea was the impact on tight junction pathway mRNA expression.[ref]

HIV and Zika’s viral replication are also regulated by m6A modifications. Silencing or reducing the m6A erasers, including FTO, can decrease the replication of the Zika virus.[ref]

The host response is modified by m6A methylation in HIV. The m6A methylation on certain spots of HIV RNA causes the host’s interferon response to be inhibited. Knocking out the FTO eraser decreased the host interferon response significantly. This is a big problem since interferon is the first line of defense in viral infections.[ref]

People with genetic variants that increase FTO have a lower likelihood of response to hepatitis C therapy. Confounding factors here include the FTO variant carriers having a higher BMI and possibly liver fat.[ref]

Other viruses that interact with m6A methylation include hepatitis C, hepatitis B, influenza A, Kaposi’s sarcoma associate virus, and SV40.[ref]

The innate immune response has to identify a viral RNA from a normal ‘self’ mRNA. One way that a virus can ‘hide’ from the host’s immune response is through m6A methylation at just the right spot on the viral RNA.[ref]

m6A methylation and COVID-19

m6A methylation is important in both the replication of the SARS-CoV-2 virus and in masking the virus from the host’s immune response. The METTL3 writer was essential for the m6A methylation.[ref]

A very recent paper from the Wuhan Institute of Virology also showed m6A methylation is important in how SARS-CoV-2 replications. The researchers concluded that the knockdown of the METTL3 (writer) methylation caused a decrease in SARS-CoV-2 replication.[ref]

Other research from Peking University also found that m6A methylation is important in SARS-CoV-2 replication. Essentially, they also conclude that reducing the writing of methyl marks on m6A decreased the replication of SARS-CoV-2.[ref]

An early 2020 research paper showed that m6A methylation on the spike protein may be one of the structural and functional differences between the original SARS and SARS-CoV-2. The SARS-CoV-2 spike protein binds to the ACE2 receptor more effectively.[ref]

Researchers at the University of California San Diego decided to modify the m6A binding site by generating mutations to see what the effect would be (May 2021 paper). Generated mutations in the m6A binding sites that disrupted binding caused an increase in the host immune response (i.e., the virus was no longer as hidden from the immune response).[ref]

Rabbit trail warning!

Methylation is dependent on the availability of methyl groups. Folate and choline are the two main dietary sources of methyl groups.

Researchers from the Broad Institute have also shown that SARS-CoV-2 replication is dependent on folate and methyl groups (aka one-carbon metabolism). They found that depleting cellular folate and, specifically, the production of methyl groups inhibited viral replication.[ref]

I wondered if drugs limiting methyl groups can limit SARS-CoV-2 replication…One way to limit methyl groups is via anti-folate drugs, which are often used for chemotherapy. It turns out that methotrexate, an anti-folate drug, inhibits the replication of SARS-CoV-2. Proguanil, an antifolate drug for malaria, and sulfasalazine, another antifolate drug, seem to inhibit the replication of SARS-CoV-2.[ref][ref]

Going clear off on a tangent: 
A lot of countries have mandated the folic acid fortification of cereal grains which increases the availability of methyl groups. (Done as a public health initiative for the prevention of folate deficiency in pregnant women.)

Here is a map of countries with mandated folic acid fortification:

Here is the wild speculation and correlation part: The areas of the world with more folic acid overlap with the areas with higher COVID deaths.
Counter argument: folic acid fortification is in processed foods, so perhaps it is food quality rather than an increased availability of methyl markers.

Does this mean that you should stop eating your leafy green veggies or avoid eating liver to deplete folate so that you don’t get the covid? No, I don’t think so…You want to be eating a healthy diet to keep your immune system in tip-top shape and keep your homocysteine levels low.

Instead, it may mean that supplemental methyl folate or folic acid isn’t beneficial when actively fighting off the virus. More research is needed, obviously.

Let’s switch gears back to the FTO variants.

FTO: Obesity and metabolism

Higher levels of FTO due to genetic variants have associations with an increased risk of obesity. Numerous studies have replicated this finding.[ref][ref][ref][ref][ref][ref]

The FTO variants that increase FTO show links to an increased risk of type 2 diabetes, independent of BMI.[ref]

Interestingly, new research now shows that people with two copies of the FTO variants linked to obesity eat at a faster rate, on average. They also tend to eat a little more food…[ref]

 Related article: FTO and weight loss

What else do FTO and m6A impact?

• FTO protects against certain aspects of ovarian aging.[ref] But it also may increase insulin resistance in ovarian granulosa cells.[ref]
• Vitamin B12 deficiency is one cause of cognitive dysfunction, especially in aging. FTO overexpression (more eraser) mediated the effect.
• The genetic variants that increase FTO (and increase the risk of obesity) protect against muscle loss and sarcopenia in the elderly.[ref]

The big question in my mind:

Does the recent FTO research negate obesity as a ’cause’ of some chronic diseases? 

The FTO genetic variants that increase the amount of FTO produced have links to an increased BMI. Conventional thinking is that obesity causes cancer, increases illnesses, and causes depression:

• Being overweight or obese is considered to be a cause of some cancers. This correlation is considered causal – e.g., you ate too much and now have cancer because of it. The American Cancer Society claims that up to 20% of cancer deaths are due to obesity.[ref]
• Being overweight or obese is correlated with being more vulnerable to viral pathogens. It seems that the thinking is – you ate too much and are therefore unhealthy and thus get sick more often.
• Being overweight or obese is correlated with depression. Sometimes it seems that the thinking is that depression causes you to overeat or that eating too much makes you feel bad about how you look and therefore causes depression…

Is the link between obesity and cancer, infectious diseases, and depression that people who are overweight are much more likely to carry the FTO genetic variant that increases FTO? Thus, the increased FTO is the upstream cause of all four conditions.

Many (most?) studies that are looking at genetic causes use statistical methods to take out the impact of comorbidities, such as higher BMI. In other words, are studies overlooking the impact of the FTO variants due to mitigating BMI?

If FTO is the ’cause’ rather than obesity as a comorbidity, researchers are factoring the FTO variant out of the equation by adjusting for BMI.

Why does it matter if being overweight causes cancer vs. carrying the FTO variant causing both overweight and cancer?

When it comes to personalizing interventions and targeting treatment, understanding the mechanism is essential.

• There are many reasons for obesity…and not everyone who is obese carries the FTO variants. Perhaps not everyone who is overweight is at an increased risk of cancer.
• Similarly, not everyone who carries the FTO variant is obese. Knowing what to target is essential to getting the intervention right.
• The ‘obesity paradox’ refers to the data showing that elderly people who are overweight are more likely to survive. Researchers have a bunch of different hypotheses of why being overweight is a benefit. But perhaps it is coincidental to carry more active FTO variants?[ref][ref]
• Generalities (e.g., obesity = increased risk of cancer) are fine when researchers are looking at whole population groups. But generalities don’t mean jack when it comes to an individual who wants to prevent a specific cancer.
• The FTO variant is now thought to be an independent link that explains the “mechanism underlying the association between mood disorders and obesity.”[ref]

Thus, if factoring out BMI (blaming obesity) has caused researchers to miss the FTO variants as a huge cancer, immune system, and depression factor – well, that could change a lot of the assumptions made in public health.

Lifehacks:

I need to emphasize again that much of the research on m6A methylation writers and erasers is new. There is still a lot to learn here, and this is a topic to revisit in a few years.

FTO is neither good nor bad – just necessary. Targeting it to strongly downregulate FTO is likely not a good idea for long-term health. The question is whether trying to slightly decrease FTO would have a positive effect on weight loss…

What to eat?

If you have too much FTO due to the genetic variants above, does this mean you should balance this ‘eraser’ with more methyl groups available for the ‘writers’? I don’t think research gives us a definitive answer on this yet, but there is some animal research that points to this conclusion.

Folate and choline:

Both folate and choline act as methyl donors in the diet. In the cell, S-adenosyl methionine (SAMe) is the molecule that donates a methyl group for methylation reactions. Sources of methyl groups for the formation of SAMe include folate (via the folate cycle) and choline (as betaine). When SAMe gives up its methyl group, it becomes SAH (S-adenosyl homocysteine). Higher levels of SAH then feed back to inhibit the m6A writer METTL3.[ref]

An animal study showed that lead toxicity, which causes learning and memory problems, affects m6A methylation. Interestingly, increasing folate could mitigate part of the learning/memory problems due to lead. The researchers concluded that this was due to folate’s effect on m6A mRNA methylation.[ref]

Green tea:

EGCG, the polyphenol found in green tea, reduces FTO and reduces the formation of fat cells – in cell studies.[ref]

Alpha-ketoglutarate and FTO:

Related Article and Topics:

BHMT: Genetic Variants that Impact Methylation 
The methylation cycle is an essential pathway for producing methyl groups, which are used by the body in a billion reactions. One role of methylation is to metabolize homocysteine, which is an amino acid that is a risk factor for heart disease.

Choline – Should you eat more?
An essential nutrient, your need for choline from foods is greatly influenced by your genes. Find out whether you should be adding more choline into your diet.

Does eating meat put you at a higher risk for colon cancer?
Recent headlines have touted that meat consumption causes colon cancer. This, of course, has set off Twitter wars between meat lovers and vegetarians, with most people left wondering how this personally affects them. Should they eliminate red meat from their diet? What is the true risk of colon cancer due to meat consumption?