We are discovering new things about the human body and human health all the time. Epigenetics isn’t a new field of research, but one that shows increasing value in providing a nuanced and dynamic view of the impact of gene regulations on health, evolution and disease.
Epigenetics refers to changes in gene activity that are heritable at the cellular level and mediated by mechanisms such as DNA methylation, histone modification and non-coding RNAs, all of which modulate chromatin architecture and accessibility without altering the underlying genetic code. It has emerged as a leading point in understanding the dynamic regulation of gene expression far beyond the static DNA sequences, providing a framework for interpreting how environmental factors, along with basic human genetics, shape phenotypic outcomes.
But beyond this, the study of epigenetics promises exciting opportunities for the field of personalised medicine and precision-focused healthcare. Understanding how epigenetics is linked to disease susceptibility and progression opens the door for advancements, including early diagnostics, targeted therapeutics, predictive modelling of disease susceptibility and even preventative techniques and treatments – all of which have the potential to transform modern healthcare and patient outcomes.
In this blog post, we’re going to take a deep dive into epigenetics, the role that it plays in biology and human diseases, and its potential for changing the face of modern healthcare.
Why do genes switch off and on?
Let’s start by learning more about genes. The human genome refers to the entire set of DNA found within a cell. It’s normally made up of four bases: adenine, thymine, cytosine and guanine, which combine to form the building blocks of DNA.
Epigenetic modifications create an additional layer of information that sits on top of the genetic code. And it is this information that determines whether genes are activated or switched off. They do this to make sure each cell in the body expresses only the genes it needs at the right time, in the right amount and in the right context. These mechanisms respond to developmental cues, environmental signals, and cellular needs, helping to shape gene expression patterns dynamically, but fundamentally, without changing the actual genetic sequence.
What is the biochemical basis of epigenetics?
The biochemical basis of epigenetics refers to the core mechanisms of exactly how gene expression is regulated in both a dynamic and context-dependent manner. While the DNA sequence offers the static code, epigenetic mechanisms determine when, where, and to what extent genes are expressed, enabling cellular specialisation, developmental plasticity, and adaptation to external signals without altering the genetic code itself.
The knowledge this provides has significant implications for human health, as well as disease. Many diseases, such as cancer and neurodegenerative diseases, metabolic conditions and autoimmune conditions, are known to involve atypical gene expression.
The network of heritable and reversible molecular modifications that regulate gene expression includes DNA methylation, histone and non-histone modifications, and coding and non-coding RNAs.
But before we look into these in more detail, let’s first get a better understanding of what is meant by developmental plasticity.
Flexibility in early development
Developmental plasticity refers to the ability of any organism to change its development in response to environmental conditions, particularly during critical growth periods, such as in the womb or during early childhood. For example, stress, toxins or even poor nutrition can trigger changes in DNA methylation or histone modifications, which can influence how genes are expressed. In some cases, genes can be switched off and on, but in others, genes can be permanently switched on with no off switch.
What this means is that early exposure to these and other triggers can potentially have long-lasting effects on human health and could contribute towards disease susceptibility – particularly for those conditions that have been identified as hereditary and/or directly affected by such triggers.
This has been proven in studies such as the Dutch Hunger Winter Epigenetics Study, which investigated how prenatal famine exposure during the Dutch Hunger Winter of 1944-45 affected the DNA methylation of people later in life. During the famine, pregnant women experience severe malnutrition. Decades later, researchers discovered that people who were in utero during this time had a considerably higher risk of developing conditions like type II diabetes, cardiovascular disease and schizophrenia as adults, compared to people born before or after the famine. This was attributed to persistent epigenetic changes, particularly affecting genes involved in metabolism and growth.
As we know, there are three primary layers to epigenetic regulation. These are:
- DNA methylation
- Histone modification
- Non-coding RNAs
Let’s look at them in more detail.
DNA methylation in an epigenetic context
DNA methylation is one of the primary mechanisms used to regulate gene expression without changing the underlying DNA sequence. It involves chemical modification of the DNA through the addition of the methyl group (CH3) to a cytosine base, forming 5-methylcytosine (5mC). The process is carried out by enzymes called DNA methyltransferases (DNMTs). It’s sometimes also referred to as gene silencing, because DNA methylation turns genes off. It does this through several processes:
- Blocking transcription factors
Transcription factors are proteins that turn genes on, activating them. Methylation usually happens at CpG sites within the DNA – locations where a cytosine (C) nucleotide is followed by a guanine (g) nucleotide, linked by a phosphate (P). When CpG sites are methylated, it’s much harder for transcription factors to bind to DNA. If they can’t bind, the gene is unable to be turned on. - Attracting methyl-binding proteins
In addition to blocking transcription factors, methylated DNA can also attract special proteins called methyl-CpG-binding domain proteins. These bind to the methylated DNA in order to provide stronger overall DNA protection. They can also recruit other proteins to further fortify the original DNA. - Chromatin compaction
DNA is wrapped around proteins called histones, forming structures called chromatin. When the additional proteins are attracted to the methylated DNA, the histones become modified, which causes the chromatin structure to condense further, making it even harder for transcription factors to get through, and ensuring the gene stays off.
While DNA methylation is almost always related to gene silencing, the exact effect can depend on where in the genome it occurs, and there are exceptions to the rule based on genomic context and cell type.
Silencing of tumour suppressor genes in colorectal cancer
Studies have found that changes in DNA methylation status have been directly linked to colorectal cancer. MLH1 is a very important gene that is responsible for fixing mistakes that happen when DNA is copied, such as tumour growth. It works to prevent harmful changes from this, which can lead to diseases, including colorectal cancer. However, if DNA methylation occurs, this gene gets switched off, preventing it from fixing the mistakes caused by DNA replication, and this could help cancer to grow and spread.
The epigenetic modification that causes this DNA methylation can act as a biomarker for early detection of colorectal cancer, as well as prediction of prognosis and therapeutic response. The application of this knowledge in a clinical setting could be used to significantly improve patient outcomes.
Histone modifications
We’ve already briefly touched on the role of histones, which are the spools of protein that DNA wraps around to form nucleosomes, which are the basic units of chromatin. This process compresses the long DNA modules into a much smaller package that can fit within the nucleus of each cell. The chromatin structure is important in terms of organisation too, as it enables efficient storage of DNA material and better access to genetic information. In all, it serves to optimise the overall efficiency of DNA within the cells of the human body. Finally, histones provide a structural barrier that helps to protect DNA from damage.
But their role doesn’t stop there. Histones play a crucial part in regulating gene expression, and modifications to histones can alter the structure of chromatin and determine whether genes are activated or repressed. They do this primarily by affecting access to genes. If access is restricted, genes are suppressed. If access is possible, genes may be activated.
Modifications usually affect the part of the histone that sticks out from the nucleotide, sometimes called the tail. Some of the changes include, but aren’t limited to:
Histone acetylation
Histone acetylation is carried out by enzymes called histone acetyltransferases (HATs), which add acetyl groups to lysine residues on histone tails. This neutralises the positive charge of the lysine, reducing its attraction to the negatively charged DNA and weakening the interaction between histones and DNA. This enables the chromatin to relax and the DNA becomes more accessible to transcription factors and other proteins that can then bind to the genes and activate them.
The reverse transcription can also occur, effectively removing acetyl groups from the DNA so that chromatin becomes more condensed, reducing accessibility to genes, repressing them.
Histone methylation
Unlike acetylation, which can only occur in histones, methylation can activate or repress gene activity depending on which amino acids in the histone are methylated and how many methyl groups are added. In effect, histone methylation acts as a molecular switch that influences the accessibility of DNA, and plays a critical role in various cellular processes, development and disease.
Histone phosphorylation
Histone phosphorylation involves the addition of a phosphate group to specific amino acids on histone tails, altering the structure of chromatin and affecting the accessibility of genes in a similar way to acetylation. By activating transcription, phosphorylation can help to repair damaged DNA as well as support gene regulation.
Coding and non-coding RNAs for fine-tuning gene regulation
There are two types of RNA – coding and non-coding. Coding RNA (mRNA) acts as a messenger, carrying instructions from the gene to the ribosomes, which are responsible for making proteins. For example, a gene tells a cell how to make insulin. The cell then makes an mRNA copy of that gene, and the ribosome reads the mRNA to build the insulin.
Coding and non-coding RNAs make up the final layer of epigenetic regulation. RNA is a molecule made from DNA that provides essential instructions for cells, telling them what they should do – whether that is making proteins or regulating which genes get used and which should lay dormant.
Non-coding RNA (ncRNA) don’t make proteins, but instead controls how genes are activated or repressed. There are many different types of ncRNA, including microRNA, which stick to mRNA to stop it from making proteins, effectively suppressing a gene, and long non-coding RNA, which can also change the chromatin structure of DNA to make genes more or less accessible. They can also fine-tune gene expression after transcription, so that it occurs on a scale rather than a definitive off/on.
How can epigenetics further our understanding of human disease?
The development of disease is influenced by a combination of different factors, with genetics a key contributor to risk, progression and variability. For example, some diseases, such as cystic fibrosis, are caused by mutations in a single gene. Individuals who inherit two copies of the mutated gene (one from each parent) will develop cystic fibrosis.
However, epigenetics provides an opportunity for understanding the complexity of human disease beyond the static information encoded in DNA sequences. While genetic mutations are well known for playing an established role in many diseases, they often fail to explain disease risk, variability of symptoms, speed of progression or treatment response. Epigenetic mechanisms provide an extra layer of gene regulation that is responsive to environmental factors, which makes them particularly valuable for detecting the molecular basis of diseases that have both genetic and environmental components, such as neurodegenerative diseases, metabolic conditions, autoimmune disorders and even cancer.
One of the most valuable contributions of epigenetic research is the identification of biomarkers. For example, some epigenetic changes are stable and detectable within individuals long before symptoms or even disease develops. One of the best examples of this is the BRCA1 gene, which is a tumour suppressor gene that plays a critical role in DNA repair and genomic stability. Mutations in the BRCA1 gene have been shown to increase the risk of developing certain cancers, particularly breast and ovarian cancers. BRCA1 mutations can be inherited from either parent and passed on to sons or daughters and are believed to be responsible for around half of inherited cases of breast cancer. While acquired mutations in BRCA1 are rare, promoter hypermethylation of BRCA1 has been observed in many cases of breast cancer in individuals that do not carry the BRCA1 mutation. This makes BRCA1 promoter hypermethylation a dynamic, non-genetic marker, which is being explored for diagnostic potential.
Epigenetics enhances our understanding of human disease by explaining phenotypic variability that cannot be accounted for by genetics alone, enabling early diagnosis, improving patient stratification, and offering novel therapeutic avenues. As our ability to map and manipulate the epigenome continues to grow, so too does the potential for developing more nuanced and effective approaches to preventing, diagnosing, and treating complex diseases.
Epigenetics and cancer
Cancer is one of the top two leading causes of death worldwide, with the World Health Organization (WHO) estimating that approximately 10 million people die from cancer globally every year. And as populations age and lifestyles change, cancer rates are predicted to grow rapidly, irrespective of the fact that we know more about cancer than ever before.
Epigenetics represents an exciting opportunity to advance our knowledge of this disease even further. In healthy cells, DNA methylation regulates gene expression to turn genes off and on as needed. However, in individuals with cancer, abnormal DNA methylation patterns can negatively impact gene expression. For example, epigenetic changes can cause the activation of oncogenes, which promote abnormal cell growth, or the silencing of tumour suppression genes, which prevent uncontrolled cell growth. Epigenetic changes have been shown to contribute to metastasis (where cancer spreads to another part of the body) and drug resistance, where cancer cells evade the effects of chemotherapy and other cancer treatments.
Changes in DNA methylation patterns are some of the earliest changes observed in cancer cells, making them valuable biomarkers for the early detection, prognosis and monitoring of cancer treatment, all of which can have a positive effect on patient outcomes. Globally, early detection is a key strategy for reducing cancer mortality and improving patient outcomes. It also reduces the severity and cost of treatment, which can help health systems, like the NHS, to cope with the rising number of cancer cases.
DNA methylation is a useful diagnostic tool for detecting early-stage cancers, often even before symptoms start to appear. Recognising this capability, some companies, such as GRAIL, are developing tests that focus on detecting methylation patterns associated with different types of cancer from a single blood sample, even before symptoms develop.
Epigenetic changes, including all three layers listed here, have been shown to play a significant role in the development and progression of lung cancer. DNA methylation is the most studied epigenetic marker in lung cancer, with research showing that genes such as RASSF1A are frequently switched off as a result of hypermethylation. A recent article in Nature Genetics showed that DNA methylation changes actively cooperate with genetic changes to drive non-small cell lung cancer progression, contributing distinct evolutionary trajectories with a joint genetic and epigenetic basis. Smoking is the core environmental factor for epigenetic changes in lung cells, accounting for more than 7 out of 10 cases of lung cancer.
Epigenetics and autoimmune diseases
Autoimmune diseases are health conditions that occur when your body attacks itself rather than defending it against illness and disease. In the UK alone, it’s estimated that over 10% of the population are affected by an autoimmune disease, such as rheumatoid arthritis, inflammatory bowel disease or type 1 diabetes.
Autoimmune disorders have a complex genetic basis, often with multiple genes contributing to disease risk by altering immune function. For example, Human Leukocyte Antigen (HLA) genes have the strongest association with autoimmunity, with some varieties linked to autoimmune conditions including type 1 diabetes, multiple sclerosis and lupus.
However, while genetic factors provide a blueprint for disease risk, epigenetic mechanisms modulate gene expression in response to environmental, hormonal and developmental cues, which helps to explain why autoimmune conditions can vary so significantly between people, including people with very similar genetic backgrounds. In determining when, where and how that risk is expressed in response to environmental and physiological stimuli, epigenetics provide an additional layer of information that is proving vital in identifying disease mechanisms, detecting biomarkers that could predict disease risk, development and response to treatment, and developing precision medicine techniques for autoimmune diseases that could drastically change patient quality of life and overall health outcomes.
For example, research into systemic lupus erythematosus (SLE) found that the disease is strongly associated with environmental triggers, like UV light, in people who are genetically predisposed to the condition. Researchers have found that CD4+T cells in people with SLE had significantly lower methylation levels compared to a healthy control group. This led to the overexpression of genes that are normally repressed, such as CD11a and CD70, which both promote T cell activation and autoantibody production. This study demonstrates how epigenetic dysregulation – in this case, DNA hypomethylation – can turn normal immune cells into autoreactive ones, contributing to disease development.
Epigenetics and neurodegenerative diseases
Neurodegenerative diseases affect millions of people worldwide. These chronic conditions are characterised by the progressive damage and destruction to the function of neurons – nerve cells that send messages across the human body, triggering every function from thinking and talking to breathing. These diseases primarily affect the central nervous system, and over time lead to a decline in cognitive, motor and behavioural abilities. Unfortunately, neuron degeneration is usually irreversible, meaning that recovery from neurodegenerative diseases is unlikely.
Research has discovered that DNA methylation plays a crucial role in the development, progression and treatment pathways of neurodegenerative, neurodevelopmental and even neuropsychiatric disorders, including conditions such as Parkinson’s Disease, Alzheimer’s Disease and amyotrophic lateral sclerosis (ALS).
Changes in 5mC and 5hmC are increasingly seen as key contributors to the molecular pathology of neurodegenerative diseases. 5mC is a methyl group added to cytosine, typically at CpG sites. It’s usually associated with gene repression when present in gene promoters. 5hmC is produced from 5mC and is primarily associated with gene activation, particularly in the brain.
It’s estimated that there are currently more than 55 million people in the world living with dementia, with Alzheimer’s disease being the most common type of the condition, accounting for up to 70% of cases. Unfortunately, it’s estimated that this number will rise to 139 million in the next 25 years, showing catastrophic growth of this debilitating, neurodegenerative disease.
Studies have found reduced global levels of 5hmC in areas of the brain affected by Alzheimer’s Disease, such as the cortex and hippocampus. 5hmC modifications are commonly found in genes that support neuroplasticity, cognitive processes and synaptic function. If there is reduced expression of these genes, synaptic function and memory formation – two key effects of Alzheimer’s Disease – may be impaired. Understanding how 5hmC levels are regulated and whether they can be restored could prove useful in developing tools and techniques for early detection and targeted epigenetic therapies that may change patient outcomes.
Epigenetics and ageing
Ageing is an inevitable and progressive part of life, but there are two different types. Chronological age refers to how long someone has been alive, in years, months and days. However, biological age is very different, and it looks at the condition of an individual’s cells, tissues and organs. There are a variety of factors that can affect biological age, and for many people, their chronological and biological ages could potentially be very different.
So, what are these factors?
Genetics
Unsurprisingly, genes play a role in influencing how well the human body manages inflammation, cellular repair and metabolic balance. However, it’s thought that genetics accounts for less than 25% of lifespan variability, meaning that other factors may be equally, if not more, important in the ageing process.
Epigenetics
Epigenetic changes like DNA methylation and histone modification can influence the rate of ageing and contribute towards age-related diseases through mechanisms such as disruption to DNA repair, increased genomic instability and cellular senescence, which is where cells stop dividing and contribute to age-related decline. Epigenetic changes accumulate with age and faster epigenetic changes have been linked to increased disease risk and mortality.
Lifestyle and behaviour
The role of diet, exercise and sleep in human health is impossible to overstate, and they are also core factors that impact the ageing process. It’s widely accepted that following a Mediterranean diet is likely to lead to slower biological ageing and a potentially longer lifespan, while regular physical activity – even walking – helps to reduce inflammation and improve mitochondrial function, which is important for regulating different metabolic pathways. Sleep is essential too, and chronic sleep deprivation prevents DNA repair, increases cortisol and accelerates cognitive decline. Choosing healthy habits is important too. For example, smoking can drastically increase oxidative stress and DNA damage, leading to faster biological ageing.
Some of the other factors known to accelerate the ageing process include psychosocial stress, which is linked to epigenetic changes in genes related to mood, inflammation and immunity, inflammation and poor immune function, and long-term environmental exposures to harmful toxins such as pollution, UV radiation and heavy metals, which have been shown to accelerate ageing and disease onset.
Epigenetics and precision medicine
With every person being different, it stands to reason that every element of healthcare, from diagnosis to treatment, may be more effective if it is targeted to the individual. This is the basis of precision medicine, which offers real hope for the future of healthcare.
Rather than a one-size-fits-all approach, precision medicine is tailored to the specific characteristics of each person, using data about their genetics, epigenetics, lifestyle, behaviours and more. This strategy enables more accurate diagnosis, risk predictions and targeted therapies based on an individual’s unique biological profile. This approach is especially important for complex diseases such as cancer, autoimmune disorders and neurodegenerative conditions, which arise from heterogeneous and interacting genetic, epigenetic and environmental factors that often drive disease onset and progression through diverse molecular pathways.
Moving away from a one-size-fits-all paradigm, advancing our knowledge of an individual’s genomic and epigenomic biology could pave the way for better disease risk profiling, earlier detection, targeted treatments with greatly improved efficacy and overall better patient outcomes. One of the best ways of achieving this is by developing an understanding of both genetics and DNA methylation with a 6-base genome.
biomodal’s epigenetic solutions
The emergence of the 6-base genome represents an opportunity to explore an expanded view of the genetic code that doesn’t only include the four canonical DNA bases of adenine (A), cytosine (C), guanine (G) and thymine (T), but also two additional epigenetically-modified bases, 5‑methylcytosine (5mC) and 5‑hydroxymethylcytosine (5hmC). This can provide researchers with a much richer, more complete and nuanced version of DNA that takes epigenetic information into the genome’s structure and regulatory potential.
This development further underscores the principle that information stored in DNA is not just limited to the static sequence, but also about the chemical modifications that shape gene function across time and tissue type. For example, disrupted distribution of 5mC and 5hmC has been associated with numerous pathological conditions, especially malignancies, where epigenetic regulation via DNA methylation is commonly altered. Shifts in methylation landscapes, through either increased or decreased methylation, often represent some of the initial molecular events in oncogenesis, underscoring the critical influence of these chemical modifications on gene activity and disease evolution.
Conventional approaches for detecting cytosine modifications, such as bisulfite sequencing combined with whole-genome sequencing, are restricted to generating a 5-base genome. While they can detect modified cytosines (cytosines which carry a 5mC or 5hmC modification), they lack the resolution to differentiate between 5mC and 5hmC. These methods are also labour-intensive and often produce lower-quality data, as they require splitting DNA samples, conducting parallel experiments, and performing multiple rounds of data analysis, leading to substantial information loss. The duet multiomics solution evoC, addresses these limitations by enabling a streamlined, single-workflow approach that accurately sequences the full 6-base genome, including all four canonical bases plus distinct identification of 5mC and 5hmC, from the same DNA fragment, using standard next-generation sequencing platforms.
