YOUR GENES | part 2
In the first part of our journey, we waded into the world of DNA, genes, the genome, genetic variants, SNPs, Nutrigenetics and Nutrigenomics. Quite a mouthful, isn't it?
As you dip your toes deeper into the waters of genetics, you'll likely encounter terms like "epigenetics" and "DNA methylation".
These can be big concepts to grasp, often thrown into conversation with little contextual life-raft. They tend to be bandied about in clinical lectures like confetti, before the topic plunges headfirst into the alphabet soup of genetic variants such as MTHFR, MTR, DAO, HNMT, DVD... (Apologies, I’m joking, that last one wasn’t a variant).
Nevertheless, in a quest for clarity, my hope is to illuminate these shadowy concepts of epigenetics and DNA methylation and to delve into what they represent, in order to help you understanding your genes and your genetic test results better, should you decide to pursue that.
So, let’s take a deep breath and dive in on part 2, starting with, what is DNA methylation?
WHAT IS dna methylation?
Every cell in your body (except red blood cells) is a repository of your entire genetic code, but despite this uniformity of genetic content, your body boasts around 200 different cell and tissue types, each playing it’s own unique role, each distinguished by its own unique phenotype.
So how does this paradox come about?
These differences in your cells are brought about by the magic of epigenetics. These mechanisms, elegant in their design, dictate what genes are expressed, and which are to be imprinted indelibly.
Epigenetics pulls on the strings of our DNA behind the scenes, governing normal gene development, expression, and regulation - animating our very physiological existence.
On that theme, DNA methylation is one of the primary puppeteers; a key process that establishes cell specificity and function.
Let’s take a look below at DNA again, you can see it winds around histones forming nucleosomes, which are then packed tighter again into chromatin fibre. This fibre then forms irregularly spaced loops, which are coiled yet again, and packed even tighter into the linear bundles that form the two sister chromatids anchored together by a centromere, making up the final chromosome.
Another way to imagine what is happening, is to picture a thread. Now, consider coiling it upon itself to create a thicker, albeit shorter, string. Then, coil that again, repeating the process until you're left with a significantly shorter, yet denser, piece of string.
This is how such an immense amount of genetic code (around 3.2 billion base pairs of DNA) can be packed away into something that is only about 85 micrometres in length (for context, the length of a human chromosome is equal to about half the diameter of a single human hair).
Anyhow, I digress. Back to methylation.
Within your DNA, methylation is a biochemical ballet where an enzyme transfers a methyl group from S-Adenosyl methionine onto cytosine residues, resulting in the formation of 5-methylcytosine (5mC).
5mC has often been referred to as the “fifth nucleotide base of DNA”, joining the ranks of adenosine (A), cytosine (C), guanidine (G), and thymidine (T). But what exactly is it and what role does it play?
5mC is essentially a dressed-up version of the nucleotide base cytosine. It allows a DNA strand to preserve the original DNA sequence, just as if cytosine remained in the base pairing. However, the gene is now adorned with a methyl group, which modifies how the gene is expressed.
Like adjusting the dials on a piece of machinery, it can make the gene faster or slower, more robust or gentle, and even decide if the gene is switched "on" or "off".
Stepping into the microscopic world of DNA, the images above describe the contrasting butting of heads that is DNA methylation and acetylation. In the image on the right, those tiny methyl groups, acting much like the world's smallest bouncers, are tightening the chromatin embrace around histones, creating a dense, exclusive club that's quite difficult to penetrate - a fortress where gene expression is a privilege, not a right.
On the other hand, in the image on the left, acetylation is the well-meaning but often pesky protagonist of this tale. You see, it sprinkles acetyl groups onto histones, causing them to lower their inhibitions and open up, much like elated party guests after the punch has been spiked. Suddenly, the DNA strand is open for business, ready to passionately transcribe genes with reckless abandon.
So below, again we see another round of this molecular tug-of-war. Methylated cytosine has been added at various gene locations along the DNA sequence, pulling the chromatin closer around histones, restricting transcription access to specific genes. Meanwhile, the acetyl groups, ever the social butterflies, have flung open the chromatin doors, inviting everyone in for a grand transcription party.
But, before you start thinking methylation is the bad guy, this plot has a twist. Much like letting in too many guests and lining up the tequila shots, dysregulated acetylation can have nasty consequences on chromosomal stability.
In moderation, acetylation is considered beneficial because it allows your cells to respond to environmental cues and is involved in important processes such as growth, differentiation, and repair. However, when dysregulated, DNA acetylation is a key contributor to various diseases, including cancer.
DNA acetylation is generally considered beneficial when it is properly regulated and contributes to normal gene expression and cellular function. However, dysregulation of acetylation processes can lead to disease states, emphasizing the importance of maintaining balanced epigenetic regulation.
Those uptight little methylation bouncers truly have everyone’s best interests at heart.
WHAT IS THE METHYLOME?
The term "methylome" refers to the full collection of DNA methylation patterns in your genetic library.
Why, you ask, is the methylome so essential? Well, DNA methylation is a critical player in the regulation of gene expression, maintaining the stability of our genome, and influencing cell differentiation. Alterations in these DNA methylation patterns can have far-reaching effects on various biological processes, and are linked to diseases such as cancer, neurological disorders, and developmental abnormalities.
Thanks to the advancements in DNA sequencing and epigenetic profiling, researchers are now able to to study the methylome comprehensively, providing a wealth of knowledge into how DNA methylation contributes to our normal physiology and how it is altered in disease states.
functions of DNA Methylation
There are two main kinds of methylation; Maintenance DNA methylation and De Novo DNA methylation.
In essence, Maintenance DNA methylation is the chief custodian of your genome's stability and thrives on predictability and routine above all else. Whereas, by contrast, de novo DNA methylation is the colourful chameleon, allowing flexibility and adaptation to better blend in with the internal or external landscape.
Maintenance DNA methylation is one of the defining epigenetic processes, where a methylation signature is successfully copied onto a newly formed DNA strand. It takes place during DNA replication within newly formed cells, ensuring that the original intended methylation pattern is faithfully reproduced to exacting standards. This process is facilitated by the enzyme DNA methyltransferase 1, or DNMT1.
Throughout life, the cells in your body are constantly being replicated, with old and damaged cells being replaced by new cells. Maintenance DNA methylation is like a meticulous librarian, ensuring every cell division retains its specific gene expression pattern. After all, we wouldn’t want to morph into a Picasso each time our skin cells replicate, would we?
However, not all change is bad.
As mentioned, De novo DNA methylation allows for adaptations in cell functions and phenotypes in response to changes in your internal or external environment. So in this scenario, new methylation sites might be added to a DNA strand during cell replication, bestowing specific functions to the replicated cell or resulting in its differentiation. This process is catalysed by the enzymes DNA methyltransferase 3 alpha, DNMT3A, or DNA Methyltransferase 3 Beta, DNMT3B.
De novo DNA methylation plays a pivotal role in embryonic development, and aids in establishing tissue-specific DNA methylomes early in life, the process gradually decreasing as we mature into adulthood. Nevertheless, de novo methylation continues thereafter to influence the differentiation of stem cells into the various types of blood cells and continues to contributes to our neuronal circuitry and memory formation.
As always, balance is key. Just as with dysregulated acetylation, disruptions in DNA methylation can lead to various disease states, including cancer.
WHAT IS THE PURPOSE OF EPIGENETICS?
Epigenetics is a fascinating dance of gene expression, choreographed by the ever-changing structure of chromatin – all without ever altering a single step in the DNA sequence.
Each cell in your body – from those in your brain to those in your bones– shares this DNA sequence, yet each one presents a unique phenotype. What's responsible for such variety? It's the grand performance of gene expression, produced by epigenetics, with DNA methylation playing the leading role.
But what prompts such alterations in gene expression? It's a biological response to a symphony of factors at play, both external and internal. Think of your diet, exercise routine, stress levels, sleep patterns, and exposure to toxins. Then, consider internal elements like age, gender, microbiome, metabolic rate, and the impacts of inflammation and disease.
Throughout your life, your body is the stage, continuously receiving chords and top notes from your surrounding and internal environments, and echoing back with the rhythm of epigenetic adaptations.
The epigenetic narrative begins in the womb, where our body's first tales are told, possibly impacting our health and wellbeing in the chapters of adulthood, and even further still, influencing the storylines of our offspring. This is a scientific hypothesis known as the Developmental Origins of Health and Disease (DOHaD).
Consider this: if the mother is deficient in nourishment during the crucial period of foetal development, the highly intuitive adaptation of her body may lead to the addition of methylation markers to the baby's DNA. These markers, like secret whispers, convey information to the baby's phenotype, enhancing its metabolic efficiency.
However, those markers will remain and affect the individual during growth, development and well into adulthood, influencing their phenotype across their lifespan, despite ever-changing environmental inputs over time.
Image source: https://www.hongerwinter.nl/portfolio-item/531/
This epigenetic backstory potentially creates a conflict between a person’s phenotype and their environment as they go through life. To demonstrate this, we look to history.
The silver lining of war's tragic aftermath often comes in the form of knowledge gained. In this case, we look to a study referred to as the "Dutch famine birth cohort".
Starting its research journey in 1994, this ongoing epidemiological pursuit delves into the health impacts experienced by Dutch children. These children were conceived and carried by mothers who survived the horrifying famine of 1944-45 in Holland during the Second World War, a period heart-wrenchingly known to survivors as the "Dutch Hunger Winter".
The study's insightful revelations so far tell us that these children, products of famine-stricken mothers, showed a plethora of negative metabolic and physiological changes. They were also more prone to chronic degenerative diseases and mortality, factors that remained unaffected by the size and weight of the baby at birth.
For these children, the experience of famine during gestation linked to less desirable levels of blood cholesterol and lipids, poor glucose tolerance, abnormal blood clotting, and compromised kidney function. They also displayed higher rates of obesity, increased risk and premature onset of Type 2 diabetes, heart disease and obstructive airway disease.
In terms of behavior, these children tended to consume a high-fat diet, showed higher blood pressure spikes in response to stress, and a higher risk of schizophrenia. It's as if their bodies continued to function under the specter of starvation long after the threat had passed, still echoing the story of their gestational past.
This story puts a spotlight on the role of epigenetics and DNA methylation as one of the key mechanisms shaping these outcomes.
Image: https://www.hongerwinter.nl/portfolio-item/531/
However, the establishment of methylation markers during foetal development is merely the opening act in the grand saga of epigenetics.
Enter stage right: Epigenetic drift. As we journey through life, our methylation markers experience a sort of wanderlust, forgetting their responsibility to maintain epigenetic marks and becoming increasingly distracted by the progressively changing environment, causing our epigenome to diverge. This often happens very slowly, as we accumulate more candles on our birthday cakes.
But closely lurking behind epigenetic drift, is Epigenetic deflection. Iniquitous external factors, the villains of our story, accelerate the rate of this epigenetic drift by corrupting DNA methylation’s good sensibilities.
A most notorious character of note, is bisphenol-A (BPA). On exposure, this plastic chemical is like a bull in a china shop, disrupting methylation markers, causing hypomethylation at specific promoter regions of genes, and generally wreaking havoc in the body.
But not all is lost...
Remember, the beauty of epigenetics is in its dynamism and reversibility.
Enter stage left: Nutritional and Lifestyle Medicine. These two heroes can have a positive influence on our epigenetic narrative, optimising DNA methylation, and nourishing the specific genes involved in methylation.
So, which characters in our genetic cast are involved in DNA methylation, and what nutrients do they need to perform their methylation magic?
Find out in part three.
REFERENCES:
ISBN: 9780323734165; PMID: 27894098; 16570849; 10555141; 23888938; 28555658; 25249537; 18955703; 33664071, 24589714; DOI: 10.1007/978-3-319-55530-0_118; 10.1016/B978-0-12-804572-5.00008-2; 10.1007/978-3-319-55530-0; 10.1002/j.1538-7305.1948.tb01338.x; DOI: 10.1126/sciadv.aao4364; DOI: 10.1016/B978-0-12-803239-8.00002-8; https://www.nytimes.com/2018/01/31/science/dutch-famine-genes.html ; https://theanalyticalscientist.com/fields-applications/a-lasting-legacy ; https://www.hongerwinter.nl, https://www.nature.com/articles/s41467-023-36019-9,
