Passed from parents to offspring and containing information that will be used to specify physical and biological characteristics, genes are specific sequences within DNA that are responsible for creating the proteins needed by the body to survive. Epigenetics is an emerging specialism within the field of gene study that considers an alternative blueprint for human development – one that is influenced by both genetic and environmental factors.
In this guide, we’ll explore epigenetics and examine why it is becoming increasingly influential in helping us understand gene activity. We’ll look at the different types of epigenetic changes, and how they can impact the human body at every stage of development.
Table of Contents
What is epigenetics?
Just how much does the environment shape a human being? That is the core question at the root of epigenetic studies. The term epigenetics was coined by developmental biologist Conrad Waddington in 1942, to describe the complex and dynamic interactions between the developmental environment and the genes leading to the development of phenotype.
At its core, epigenetics focuses on the chemical changes to DNA that have a profound impact on gene activity and cellular function but without physically affecting the DNA sequence. These modifications occur through different epigenetic mechanisms that act as biological switches, turning genes off and on. The core mechanisms of epigenetic inheritance are DNA methylation, histone modification and non-coding RNA action. What this means is that while the genetic code itself remains unchanged, the way that genetic information is transmitted and interpreted by cells can be modified.
Certain epigenetic changes are known to be temporary and reversible, providing promising avenues of research into disease understanding, prevention and treatment strategies. These changes can be triggered by various factors, including exposure to metals, air pollution, organic pollutants and electromagnetic radiation, demonstrating that environmental influences can significantly impact our biological configuration.
As we delve deeper into understanding epigenetics and its impact on gene expression, we’re becoming acutely more aware of its importance; in particular, the role it plays in development during childhood. Studies show that children are particularly sensitive to epigenetic modifications, as experiences very early in life, when the brain is developing most rapidly, can cause epigenetic changes, and these changes can have a lasting impact on health, personality and even physical capabilities. Studies of epigenetic profiles in twins have revealed environmentally-induced differences that have resulted in two very unique individuals.
Epigenetics in gene expression
All genes contain instructions which essentially tell each cell what functions to perform. However, these functions aren’t in a constant state of transmission. Instead, they can be turned off or on. Turning genes on is a process that is known as ‘gene expression’ while turning them off is referred to as ‘gene silencing’. But while the genetic population of humans is 99% identical, we each have our own unique characteristics that make us, us.
When gene expression turns a gene on, it tells cells to make ribonucleic acid (RNA) and proteins. RNA is a molecule essential for most biological functions, including coding, regulation and expression of genes. It’s present in all living cells, and there are different types of RNA to serve different functions, including:
- messenger RNA (mRNA) which carries the coding sequence for protein synthesis.
- ribosomal RNA (rRNA) which form the core of a cell’s ribosomes (the structures in which protein synthesis takes place).
- transfer RNA (tRNA) which carries amino acids to the ribosomes during protein synthesis, and these amino acids are used to determine protein structure (which in turn dictates biochemical function).
Gene expression is thought to be heavily influenced by external conditions, and our bodies will adapt gene processes in response to changes in our environment. Some of the external factors that could influence gene expression via epigenetic changes include:
- smoking
- exercise
- family history
- diet
- toxins
- stress levels
Knowing that a cell is expressing certain genes provides valuable information about how a cell is functioning. It also provides insights into which genes are involved in specific cellular behaviours. This can be helpful when it comes to understanding certain diseases, why they form and how they could potentially be prevented.
Types of epigenetic changes
Firstly, it’s important to remember that epigenetic changes are reversible and do not change the sequence of DNA bases. Instead, they change how your body reads a DNA sequence. Some epigenetic changes remain in place as genetic information passes down through generations. This is known as epigenetic inheritance.
Three classes of epigenetic regulation exist.
DNA methylation
DNA methylation is when small chemical groups called methyl groups attach to DNA. When methyl groups form on a gene, the gene is silenced and doesn’t produce any protein. Methyl groups are highly stable (only between 10-20% on average vary over time) and although they have low reactivity, they still have a significant influence on cellular function.
DNA methylation occurs at the C5 position of the cytosine to form 5-methylcytosine. This happens during gametogenesis and after fertilisation. After each cell division, methylation markers are maintained by the DNA methyltransferases DNMT1, DNMT3A and DNMT3B. It can be influenced by environmental factors such as diet, hormones, stress, drugs or exposure to environmental chemicals. If DNA becomes unmethylated, the barrier to gene activation is removed and it can be ‘switched on’.
DNA methylation has both positive and negative effects on human health, depending on exactly which genes become methylated. For example, the BRCA1 and BRCA2 genes can protect against certain cancers (and are best known for their link to breast cancer). However, when these genes become methylated, their function is restricted and someone with methylated BRCA1 and BRCA2 genes is at increased risk of developing breast cancer.
Studies show that healthy methylation patterns are linked with normal human development, while irregular patterns can lead to epigenetic dysfunction, increasing the risk of neurodevelopmental disorders.
DNA hydroxymethylation
Another type of epigenetic modification, DNA hydroxymethylation helps to ensure genomic stability. It is closely linked with the demethylation process, and although it has previously been considered as simply an intermediate step on the pathway to demethylation, recent evidence shows that hydroxymethylation has its own important and distinct biological role. Methylation typically represses gene activity, while hydroxymethylation is more closely associated with active gene expression and DNA repair.
Histone modifications
Chromosomes are found in the nucleus of the majority of cell types within our body and are made up of DNA that is tightly coiled around proteins. These proteins are called histones, and they give chromosomes a more compact shape. Changes to histones will determine how tightly or loosely DNA will wrap itself around them, and this will directly affect cell behaviour. Research states that there are at least nine different types of histone modification. Three of the most frequently occurring include:
Acetylation
This occurs when an acetyl group attaches to an amino acid residue of a histone, specifically lysine or arginine. Histone acetylation facilitates gene transcription – where an RNA copy of a DNA sequence is made, triggering the process of gene expression.
Deacetylation is the process of silencing the gene and is the removal of acetylation groups from histones.
Methylation
Unlike acetylation, which only occurs in histones, methylation can occur in DNA and histones. When methyl groups attach to a histone, it will either trigger activation or silencing depending primarily on the location of the residues.
Phosphorylation
This refers to the addition of a phosphate group to a histone and mostly occurs in the serine or glycine residues. Histone phosphorylation is generally thought to activate transcription. The primary role of this process is to support gene regulation, but phosphorylation can also help repair damaged DNA.
For all histone modifications, there are processes through which chemical groups are either added or removed from the histones. They are sometimes known as ‘writers’ and ‘erasers’. Writers are enzymes that add chemical groups to histones, while erasers remove them.
Noncoding RNA action
RNA, or ribonucleic acid, works closely with DNA to ensure that cells grow and function properly. While DNA contains all of the instructions that cells need, RNA is responsible for following these instructions, which it does by copying genetic code to produce the necessary proteins. A non-coding RNA is a functional RNA molecule that is not used as a template for making proteins. Instead, RNA molecules have other important functions in action such as regulating gene expression. They play a role in controlling which genes are activated or silenced, as well as in the structure of chromosomes.
RNA strands can also be modified through the process of methylation. When a methyl group is added to an RNA molecule, the original instructions don’t change, but it does become easier for cells to understand them and what they need to do. Methylation can control factors such as how long the RNA lasts before it gets broken down, and how much protein is made. Essentially this is an added layer of control in regulating gene activity to support normal development and protect our bodies from disease.
Messenger RNA (mRNA) and microRNA (miRNA) – what’s the difference?
Messenger RNA (mRNA) is responsible for transporting genetic instruction from DNA to the protein-making mechanisms stored within cells. mRNA is created through transcription – a process by which a cell creates a messenger molecule from a DNA template. During transcription, RNA polymerase reads the DNA sequence of a gene and synthesises a complementary mRNA module. This carries the genetic information from the DNA found in the cell’s nucleus to the ribosomes in the cytoplasm, where it acts as a template for protein synthesis.
MicroRNAs (miRNAs) are a group of non-coding RNAs that play a key role in RNA silencing and gene expression. By binding to mRNAs, microRNAs can block the mRNA from being transformed into a protein or target it for cell degradation, influencing the level of certain proteins within the cell and ensuring that the right number of proteins are made, regulating normal gene function and helping to prevent disease.
Uncovering the genome through epigenetics
The genome is the entire set of DNA instructions found in a cell. The human genome is typically composed of four bases – adenine, thymine, cytosine and guanine – which pair up to form the building blocks of DNA.
Epigenetic modifications like methylation create an additional layer of information to the traditional genome. This sits on top of the genetic code, influencing how genes are activated or silenced in different cells and at different times. This additional layer of regulation plays a role in controlling various biological processes, development and responses to the environment, without altering the genetic sequence.
In human studies, researchers have linked the epigenetic modification 5-hydroxymethylcytosine (5hmc) to gene expression, and it is now recognised as an important epigenetic mark in a number of developmental and neurological diseases, including Alzheimer’s disease, amyotrophic lateral sclerosis (ALS), fragile X-associated tremor/ataxia syndrome, Friedreich ataxia, Huntington’s disease and Parkinson’s Disease.
A deeper analysis of the way epigenetic modifications add layers to the genome could help extend our understanding of specific disease areas, paving the way for the development of more successful preventative and/or targeted treatment therapies.
DNA damage and repair
The structure of chromatin plays a crucial role in regulating gene expression, and many other cellular processes, including DNA repair.
Damage to DNA is defined as anything that alters its chemical structure, causing mutations that affect its ability to function or fulfil its purpose. There are many things that can cause DNA damage including environmental factors, like exposure to ultraviolet light, radiation and tobacco smoke. Oxidative stress from exposure to free radicals, and damage from metabolic or hydrolytic processes can also occur.
Common types of DNA damage:
Single-strand breaks (SSBs): where one strand of the DNA double helix breaks, and often associated with damaged or mismatched 5’ and/or 3’ termini at the sites of SSBs and related to oxidative stress.
Double-strand breaks (DSBs): which is the most dangerous form of DNA damage and can lead to cancer. This happens at specific sites in the genome during replication.
Chemical modifications: where the base in the DNA is damaged. Some chemical modifications can directly cause DNA mutations by changing the sequence of nucleotides, while others can lead to the formation of DNA adducts. This can result in profound effects on cellular processes and genomic integrity, including mutations and the development of various diseases.
Crosslinking: refers to the formation of covalent bonds between two strands of DNA, or between DNA and other molecules, leading to interference in processes like DNA replication and transcription. It can also prevent DNA repair mechanisms from correcting the damage, potentially causing other mutations or harmful cell effects.
Thymine dimers: where UV light causes abnormal covalent bonds between adjacent thymine bases, instead of bonding with their complementary adenine bases on the opposite DNA strand. Typically caused by exposure to UV light, these dimers can also interfere with DNA replication and transcription, as well as leading to skin cancer and other mutations.
If damaged DNA isn’t repaired, it can affect replication and transcription, and genomic mutations can be carried over to offspring. To prevent this and restore the integrity of the DNA, your body will try and repair damaged cells. There are several mechanisms through which this can be achieved, including:
Mismatched repair
This corrects errors that occur during DNA replication, detecting and removing mismatched bases to ensure that the newly synthesised DNA strain matches the original template.
Base excision repair (BER)
This process repairs DNA damage caused by chemical modifications, such as oxidised bases. Specialised enzymes identify and remove the damaged base, which is followed by the insertion of the correct base by DNA polymerase.
Nucleotide excision repair (NER)
To repair DNA damage caused by chemical modifications like UV-induced thymine dimers, proteins identify and excise the damaged DNA and DNA polymerase replaces it with the correct sequence.
The key difference between base excision repair and nucleotide excision repair lies in the type of DNA damage that they repair. While BER focuses on smaller, subtle alterations, NER deals with larger, bulkier lesions.
In some cases, your body can directly reverse the damage, rather than having to use the mechanisms above. The aim is for DNA to be repaired before replication to prevent it from being passed on to offspring. If the cell reaches the replication fork, error-prone repair could prove effective, as the pathways it follows prioritise speed and efficiency over accuracy. This means that it can result in changes to the DNA sequence that introduce mutations or lead to genomic instability. For this reason, an error-prone repair mechanism is best considered when cells are heavily damaged, but the benefit of rapid repair outweighs the risk of developing errors.
What happens if DNA can’t be repaired?
If DNA is unable to be repaired, one of three things will happen.
- Cells will become senescent and non-functional. However, the accumulation of senescent cells over time can contribute to age-related diseases.
- Cells will die a cell death and become apoptotic. Apoptosis is critical for maintaining tissue homeostasis and eliminating potentially harmful cells that may be undergoing abnormal growth or suffered irreparable damage.
- Cells will become malignant. DNA mutations play a significant role in driving the aberrant growth and behaviour of cancer cells.
Cells can suffer anywhere from 10,000 to one million DNA-damaging events per day, demonstrating exactly how much the integrity and stability of DNA are being threatened by exogenous factors on a day-to-day basis.
Examples of epigenetics and disease
Understanding the complex genetic, environmental and physiological factors that contribute to disease is crucial for developing effective preventive strategies and treatment modalities. By dissecting the underlying mechanisms driving disease pathogenesis, it may be possible to tailor interventions to help prevent them or to create more personalised targeted treatments that contribute towards improved patient outcomes. In some cases, the possibility of identifying gene mutations that would ordinarily be passed down to future offspring provides us with the knowledge to make informed choices about procreation, as well as what to expect should we choose to have offspring that could potentially have inherited DNA mutations.
Inheriting genetic conditions from parents involves a complex interplay of genetic factors. For dominant inherited disorders, only one parent needs to have a DNA mutation for the child to potentially develop the same condition. If a disorder is recessive, it requires two copies of an abnormal gene for the disorder to be present in the offspring. Individuals who inherit one abnormal gene copy are usually carriers but typically don’t develop symptoms of their own. For this reason, many people don’t realise that they are carrying a genetic mutation until their child develops symptoms associated with a genetic disorder.
Can epigenetic changes be passed down to offspring?
In theory, environmental factors should only cause epigenetic changes in the person who has been exposed. However, research suggests that in some cases, epigenetic changes in a parent could lead to increased disease susceptibility in their offspring. While they don’t alter the DNA sequence, they do control gene activation. For example, a mother who has gestational diabetes may find that their child is more likely to develop diabetes later in life.
Epigenetics and cancer
When a gene mutation occurs in a gene that is supposed to control or limit cell growth, it can lead to uncontrolled cell division which could contribute towards the development of cancer. Usually, tumour suppressor genes play a role in regulating cell growth to help prevent the formation of tumours, but if a mutation affects these genes, they may no longer function properly to control cell growth effectively. Mutations in genes such as TP53, RB1 and PTEN are known tumour suppressor genes that can disrupt the cell cycle and promote cell proliferation.
Research has identified strong links between epigenetic changes and cancer development. The most obvious is exposure to tobacco, with evidence to confirm that smoking causes at least 16 different types of cancer and is the biggest cause of cancer worldwide. Studies also show that the greater your tobacco exposure (the more you smoke in a day) the higher your risk of cancer.
Similarly, epigenetics has been shown to play a crucial role in the development of melanoma, the most aggressive form of skin cancer that is caused by genetic mutations in melanocytes. Several factors are believed to be involved in melanoma progression, including genetic alteration, the processes of damaged DNA repair and changes in mechanisms of cell growth and proliferation.
Epigenetic treatments are a developing area within cancer research. Aimed at modifying gene expression without altering the underlying DNA sequence, they seek to stabilise irregular DNA methylation patterns to restore normal gene expression and slow or even reverse cancer progression. Currently, clinical trials focusing on epigenetic therapies are ongoing.
Epigenetics and neurodegenerative diseases
Epigenetic changes have also been linked to the development and progression of key neurological disorders, including Alzheimer’s Disease and Parkinson’s Disease. Both DNA methylation and histone modifications have been implicated in the progression of neurodegenerative diseases. However, research suggests that histone modification has the greatest influence, with evidence suggesting an association with learning, memory and cognitive function.
Epigenetic changes associated with neurodegenerative diseases can occur at any stage of life, from early development through to adulthood. Some may be present even before birth, particularly those in the form of 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC), while others are a definitive result of environmental exposure. As with cancer, the more we understand the role that epigenetic modifications may play in the development of neurological conditions, the more successful we may be in predicting patterns, prevention and developing targeted therapies that improve patient quality of life.
Unlocking the potential of epigenetic therapy
As our understanding of epigenetics and its importance continues to improve, the potential for targeted epigenetic therapies continues to grow exponentially. These therapies could eventually alter epigenetic marks to combat unhealthy patterns of gene expression that could cause disease or other serious health complications, reducing the disease burden for future generations.
Research shows that their potential applications are vast, but perhaps the most promising avenue is in cancer treatment. For example, DNA methyltransferase inhibitors can act as chemotherapeutic agents to disrupt methylation processes, leading to the reactivation of tumour-suppressing genes in cancerous cells. However, as is common with chemotherapeutic agents, clinical studies have revealed possible side effects to this treatment, which include a heightened risk of infection and gastrointestinal issues. As with most therapies, healthcare providers will need to carefully balance risk and reward with future epigenetic treatments to ensure patients achieve the optimal benefit.
Another important therapy that highlights the incredible potential of epigenetic treatment are histone deacetylase inhibitors (HDACi), such as vorinostat and romidepsin. HDACi can reactivate previously silenced genes to promote healthy gene expression patterns by preventing the removal of acetyl groups from histones. While further research is needed to determine the efficacy of such therapies, early trials suggest that HDACi could help to treat both neurological and psychiatric conditions.
Understanding the link between epigenetics and ageing
We know that epigenetics contributes heavily to the early developmental stages of life, but how does it impact the body as we age?
As we age, epigenetic changes can accumulate in our cells, leading to alterations in gene expression and overall cellular function. DNA methylation generally decreases with age, while region-specific changes in methylation patterns can occur that could activate or silence certain genes. The balance of histone acetylation and methylation can also alter with age, changing chromatin structure and gene regulation. In fact, changes in histone modifications have been linked to gene expression patterns that are associated with both ageing and age-related diseases.
Furthermore, recent research has also found evidence that methylation can be used to accurately measure a person’s biological age – this is known as an epigenetic clock. This is a field that’s capturing the attention of researchers who feel this clock could be an effective biomarker of ageing at the least, and potentially hold the key to age-reversing treatments and extending the human health span at the most.
Understanding the dynamics of epigenetic modifications during the ageing process could provide insights into the molecular mechanisms of age-related diseases that could eventually lead to new preventative measures, as well as advancing therapeutic intervention techniques.
While it’s clear that ageing plays an important role in determining methylation patterns, it’s not the only factor. Lifestyle choices are significantly influential to these genetic outcomes. This tells us that our genetic destiny isn’t pre-determined, but that it is possible to influence health outcomes by making better lifestyle choices. In addition, since epigenetic mechanisms don’t leave a permanent mark on our DNA, there is the possibility for more treatments to effectively reverse these changes, which could have a monumental impact on how future generations grow old.
