Hello! This week's educational post is on DNA methylation. Note that DNA methylation functions a bit differently in plants vs animals. This post will be more plant-centric since that is what I study.
DNA methylation refers to the addition of a methyl group (one carbon molecule) to the 5' position of a cytosine base in the DNA. This is a type of epigenetic mark, or a heritable genetic modification without a change in DNA sequence (Takuno & Gaut, 2012). It alters the expression of genes through transcriptional silencing, usually by preventing the binding of polymerase. However, the exact ways methylation regulates and is regulated can differ depending on context (Neiderhuth & Schmitz, 2016). There are three contexts in which DNA methylation can occur: CG, CHG, and CHH, where H represents A, T, or C (Neiderhuth & Schmitz, 2016).
Methylation in the CG context, known as CpG methylation, is the most stable of the three contexts. After DNA replication occurs, VIM1-5 recognizes hemi-methylated CG sites and recruits the methyltransferase MET1 to methylate the unmethylated strand (Neiderhuth & Schmitz, 2016). CpG methylation around the transcriptional start site causes transcriptional silencing, while CpG methylation in the gene body is associated with active, and even increased, transcription (Neiderhuth & Schmitz, 2016).
Methylation in the CHG context is the second most stable. It is maintained by the methyltransferase CMT3, which depends on the H3K9me2 histone modification (I'll go over histone modifications for my next educational post) in a positive feedback loop that maintains the locations of both these epigenetic marks (Neiderhuth & Schmitz, 2016). This feedback loop can be broken by the histone demethylase IBM1, causing transcription to become reactivated (Neiderhuth & Schmitz, 2016).
CHH methylation cannot be maintained after DNA replication due to its asymmetry: lack of a guanine on the methylated strand means there is no cytosine to methylate on the opposite strand (Neiderhuth & Schmitz, 2016). CHH methylation is always established de novo by the methyltransferase CMT2 or through the RNA-directed DNA methylation (RdDM) pathway (Neiderhuth & Schmitz, 2016).
De novo DNA methylation for all three contexts can be mediated by the RdDM pathway (Zhang et al, 2018). In this process, short-interfering RNAs (siRNAs) work together with scaffold RNAs and a variety of proteins to guide the methyltransferase DRM2 to target regions for methylation (Zhang et al, 2018).
Transcriptional regulation through DNA methylation is important for a variety of processes related to plant development and genome stability. Specifically, it has been shown to be involved in transposon silencing (Slotkin & Martienssen, 2007), fruit ripening (Xiao et al, 2020), genetic imprinting (Rodrigues et al, 2013), and aging (D’Amico-Willman et al, 2024).
(Neiderhuth & Schmitz, 2016)
Important Terms: DNA methylation, epigenetics, cytosine, transcription, methyltransferase
Welcome back! In July, we are shifting gears to talk about the molecular mechanisms mediating the link between genetics and the environment—epigenetic markers. Check it out and subscribe!
Ageing is the gradual decline in organismal fitness that occurs over time leading to tissue dysfunction and disease. At the cellular level, ageing is associated with reduced function, altered gene expression and a perturbed epigenome. Somatic cell reprogramming, the process of converting somatic cells to induced pluripotent stem cells (iPSCs), can reverse these age-associated changes. However, during iPSC reprogramming somatic cell identity is lost, and can be difficult to reacquire as re-differentiated iPSCs often resemble foetal rather than mature adult cells. Recent work has demonstrated that the epigenome is already rejuvenated by the maturation phase of reprogramming, which suggests full iPSC reprogramming is not required to reverse ageing of somatic cells. Here we have developed the first ″maturation phase transient reprogramming″ (MPTR) method, where reprogramming factors are expressed until this rejuvenation point followed by withdrawal of their induction. Using dermal fibroblasts from middle age donors, we found that cells reacquire their fibroblast identity following MPTR, possibly as a result of persisting epigenetic memory at enhancers. Excitingly, our method substantially rejuvenated multiple cellular attributes including the transcriptome, which was rejuvenated by around 30 years as measured by a novel transcriptome clock. The epigenome, including H3K9me3 histone methylation levels and the DNA methylation ageing clock, was rejuvenated to a similar extent. The magnitude of rejuvenation instigated by MTPR is substantially greater than that achieved in previous transient reprogramming protocols. MPTR fibroblasts produced youthful levels of collagen proteins, suggesting functional rejuvenation. Overall, our work demonstrates that it is possible to separate rejuvenation from pluripotency reprogramming, which should facilitate the discovery of novel anti-ageing genes and therapies. ### Competing Interest Statement W.R. is a consultant and shareholder of Cambridge Epigenetix. T.S. is CEO and shareholder of Chronomics. All other authors declare no competing interests.
Abstract
Ageing is the gradual decline in organismal fitness that occurs over time leading to tissue dysfunction and disease. At the cellular level, ageing is associated with reduced function, altered gene expression and a perturbed epigenome. Somatic cell reprogramming, the process of converting somatic cells to induced pluripotent stem cells (iPSCs), can reverse these age-associated changes. However, during iPSC reprogramming somatic cell identity is lost, and can be difficult to reacquire as re-differentiated iPSCs often resemble foetal rather than mature adult cells. Recent work has demonstrated that the epigenome is already rejuvenated by the maturation phase of reprogramming, which suggests full iPSC reprogramming is not required to reverse ageing of somatic cells. Here we have developed the first ″maturation phase transient reprogramming″ (MPTR) method, where reprogramming factors are expressed until this rejuvenation point followed by withdrawal of their induction. Using dermal fibroblasts from middle age donors, we found that cells reacquire their fibroblast identity following MPTR, possibly as a result of persisting epigenetic memory at enhancers. Excitingly, our method substantially rejuvenated multiple cellular attributes including the transcriptome, which was rejuvenated by around 30 years as measured by a novel transcriptome clock. The epigenome, including H3K9me3 histone methylation levels and the DNA methylation ageing clock, was rejuvenated to a similar extent. The magnitude of rejuvenation instigated by MTPR is substantially greater than that achieved in previous transient reprogramming protocols. MPTR fibroblasts produced youthful levels of collagen proteins, suggesting functional rejuvenation. Overall, our work demonstrates that it is possible to separate rejuvenation from pluripotency reprogramming, which should facilitate the discovery of novel anti-ageing genes and therapies.
Epigenetics is a fast-growing field that truly goes “above and beyond” genetics as its name suggests. This field of research involves studying the changes in gene expression that do not result from changes in the sequence of DNA. It is fascinating to discover that there is much more to our DNA than the astonishing 3 billion base pairs packed into each one of our cells. A strand of DNA does not exist alone in the nucleus but is wrapped around protein octamers known as histones. These units, called nucleosomes, are wound into increasingly organized structures. From here, it only gets more complicated because this organization is dynamic. DNA and histones can be chemically modified in several ways that initiate changes in structure and thus changes in expression of specific genes. For instance, DNA methylation of cytosine nucleotides is known to cause the silencing of a gene. This is accomplished directly when the methyl group blocks a transcription factor from binding to a promoter or indirectly when the methylation recruits cellular machinery that induces gene silencing histone modifications. Histone modifications are the other route of epigenetic control of gene expression, which involves the addition of chemical groups to lysine residues of histone proteins. This alters the structure of the chromatin and changes the availability of regulatory DNA to be accessed by transcription machinery. There are dozens of histone modifications that comprise a code that changes patterns of gene expression. One well-known example is histone acetylation which increases gene expression by causing DNA to be less tightly wound around histones and thus more accessible for transcription. Researchers are only beginning to elucidate the epigenetic changes at the DNA and histone modification levels that control gene expression.
Epigenetic modifications are implicated in the many different areas of neuroscience. They are dynamic and vulnerable to disruption and represent the intersection of our genes and the environment. For example, epigenetic changes are known to play a role in psychiatric disorders such as schizophrenia. Epigenetic changes can occur throughout life but are thought to be especially important during the early phases of development. DNA methylation and histone modifications are implicated in several other neurobiological processes, such as learning and memory. These processes involve long term changes in the brain in response to environmental cues, so it is plausible that changes in gene expression due to epigenetic changes may be implicated. Epigenetic changes during memory formation may be influenced by the activity of CREB. CREB is a transcription factor that is implicated in memory formation. Knockout of this cAMP response element-binding protein in mice causes them to display learning and memory deficits. It is hypothesized that contextual fear conditioning and the resulting long term potentiation cause changes in CREB which then alters gene expression by altering epigenetic marks.
Several types of epigenetic changes have been observed in animal models of learning and memory. For instance, it has been demonstrated that there is an increase in DNA methylation after behavioral fear conditioning, which suggests that learning causes silencing of DNA (Molfese, 2011). This illustrates the counterintuitive notion that learning involves the suppression of genes that were active in addition to activating genes that were suppressed. One theory based on this research is that certain genes may be actively suppressing memory formation until learning is needed. When a context arises where learning would prove beneficial, these genes are turned off via methylation (Molfese, 2011).
Other studies have examined histone modifications in relation to learning and memory and reported significant findings indicating that this category of epigenetic changes is important for long term memories as well. For instance, pairing a shock with short exposure to a new context causes one type of histone acetylation while a longer exposure to the context followed by a shock causes acetylation of a different histone (Molfese, 2011). These results indicate that different types of learning are due to different types of epigenetic changes. Additionally, the acetylations observed in these experiments lasted only briefly, just 1-2 hours. However, the researchers noted that certain chemicals can prolong this acetylation. Finally, histone methylation is also thought to play a role in memory formation. Patterns of histone methylation in area CA1 of the rat hippocampus are altered following contextual fear conditioning and other memory tasks (Molfese, 2011). Interestingly, mice that lack specific methyltransferases show deficits in memory, which supports the importance of these modifications in the formation of memories.
This field of research strongly suggests that a variety of epigenetic alterations are important for the formation of memories. Alterations that cause deficits in the brain’s ability to institute these modifications following an event impair the ability to form memories. Additionally, it was demonstrated that certain molecules can enhance memory acquisition. Research on the contribution of epigenetic modifications in the context of memory formation is a growing field that can have important implications in understanding memory consolidation and the failure of the system to work properly. The implications of this research could be significant in that it could lead to therapies for those with disorders that cause disruption in memory formation as well as treatment for healthy individuals to bolster memory performance.
References:
Molfese, D. L. (2011). Advancing Neuroscience Through Epigenetics: Molecular Mechanisms of Learning and Memory. Developmental Neuropsychology, 36(7), 810–827. doi: 10.1080/87565641.2011.606395
Mysterious DNA Modification Seen in Stress Response
With advances in genomics, scientists are discovering additional components of the DNA alphabet in animals. Do these unusual chemical modifications of DNA have a special meaning, or are they just signs that cellular machines are making mistakes?
The research is in Nature Communications. (full open access)
Bipolar disorder affects nearly 6 million Americans and is characterized by drastic shifts in mood, activity levels, and energy, which influences an individual’s ability to carry out daily tasks. It’s a dangerously misunderstood disease and can be easily misdiagnosed. The extreme adjustments in mood – known as mania and depression – are more severe than the typical ups and downs that many people experience. Researchers are finding that something called premature epigenetic aging might play a role in this disease [more...]
A group of researchers from The University of Texas Health Science Center (UTHealth) at Houston reported a connection between accelerated epigenetic aging and bipolar disorder. The results, published in Translational Psychiatry, could explain why people suffering from bipolar disorder are more likely to die from age-related diseases.
Epigenetic Changes at Birth Could Explain Later Behavior Problems
Epigenetic changes present at birth - in genes related to addiction and aggression - could be linked to conduct problems in children, according to a new study by King's College London and the University of Bristol.
The research is in Development & Psychopathology. (full access paywall)
Can Your Lifestyle Influence Your Genes? Understanding the Power of Epigenetics
For years, many people believed that the genes they inherited completely determined their health. If diabetes, obesity, or high blood pressure ran in the family, developing those conditions seemed unavoidable. However, modern research has revealed a different perspective. While your genes provide the blueprint, your daily habits can influence how those genes function.
This fascinating field of science is known as epigenetics. It explains how nutrition, physical activity, sleep, stress management, and environmental factors can affect gene activity without changing the DNA itself. Understanding epigenetics can help you make informed lifestyle choices that support long-term health and overall well-being.
What Is Epigenetics?
Every cell in your body contains DNA, which carries the instructions needed for growth, repair, and normal body functions. Epigenetics refers to the natural process that controls whether certain genes are active or inactive.
A simple way to understand this is to think of your DNA as a large instruction manual. Epigenetics acts like bookmarks and sticky notes that tell your body which instructions to use and which to skip. The instructions remain the same, but the way they are read can change over time.
One of the most studied epigenetic processes is DNA methylation, where small chemical markers attach to DNA and influence gene activity. These changes do not alter your genetic code but can affect how your body responds to disease, metabolism, and aging.
Genetics vs. Epigenetics: What's the Difference?
Many people confuse genetics with epigenetics, but they are not the same.
Genetics refers to the DNA sequence inherited from your parents. This genetic code generally remains unchanged throughout life.
Epigenetics, on the other hand, involves changes in how those genes are expressed. These changes are influenced by lifestyle choices, environmental exposures, nutrition, stress, and other everyday factors.
This means that although you cannot change the genes you inherit, you can often influence how they function by adopting healthier habits.
How Lifestyle Affects Gene Expression
Research continues to show that daily routines have a significant impact on gene activity. Small, consistent lifestyle improvements may encourage beneficial genes while reducing the activity of genes linked to chronic illness.
Several habits play an important role in healthy gene expression:
Eating a balanced diet rich in whole plant foods
Engaging in regular physical activity
Maintaining healthy sleep patterns
Managing stress effectively
Limiting exposure to harmful environmental toxins
Together, these habits create an internal environment that supports healthy cellular function and overall wellness.
The Role of Nutrition in Epigenetic Health
Food provides much more than energy. Many nutrients directly support the body's natural epigenetic processes.
Leafy green vegetables, beans, lentils, seeds, whole grains, and colorful fruits contain vitamins, minerals, antioxidants, and natural compounds that help maintain healthy DNA regulation.
Certain nutrients—including folate, vitamin B12, and choline—participate in methylation, one of the body's key epigenetic mechanisms. Foods naturally rich in these nutrients can support normal gene regulation and healthy metabolism.
A diet based on a wide variety of minimally processed plant foods also promotes a healthy gut microbiome. Beneficial gut bacteria produce compounds that may positively influence immune function, metabolism, and inflammation through epigenetic pathways.
Epigenetics and Obesity
Scientists have found growing evidence linking obesity with epigenetic changes. Excess body fat, chronic inflammation, and unhealthy dietary habits may influence the activity of genes involved in fat storage, insulin regulation, and metabolic health.
The encouraging news is that these changes are not always permanent. Weight management through balanced nutrition, regular exercise, and healthy lifestyle habits may improve many of these epigenetic markers over time.
This highlights an important principle of epigenetics: lifestyle choices can gradually influence how certain genes behave.
Can Fasting Influence Gene Activity?
Researchers have also explored the relationship between fasting and epigenetics. Under appropriate medical supervision, structured fasting approaches have shown potential effects on metabolic pathways involved in energy use and insulin sensitivity.
Studies suggest that fasting may activate cellular repair processes while influencing genes associated with inflammation, metabolism, and energy balance.
Although more research continues, these findings demonstrate how lifestyle interventions may affect gene expression alongside other health benefits.
Stress, Sleep, and Gene Expression
Nutrition is only one part of the epigenetic picture. Chronic stress and poor sleep can also influence how genes function.
Long-term stress increases the production of stress hormones, which may contribute to inflammation and metabolic imbalance. Relaxation practices such as meditation, yoga, deep breathing, and mindfulness may help reduce stress while supporting healthier biological responses.
Sleep is equally important. During sleep, the body repairs tissues, regulates hormones, and maintains normal cellular function. Consistently getting around seven to eight hours of quality sleep helps support healthy metabolic and epigenetic processes.
Everyday Habits That Support Healthy Epigenetics
Improving your gene expression doesn't require dramatic changes. Small, sustainable habits often have the greatest long-term impact.
Some practical ways to support healthy epigenetics include:
Eat a variety of colorful fruits and vegetables every day.
Include legumes, beans, lentils, nuts, seeds, and whole grains in your meals.
Stay physically active with regular exercise.
Practice meditation, yoga, or other stress-reduction techniques.
Aim for consistent, high-quality sleep.
Reduce intake of heavily processed foods.
Minimize unnecessary exposure to pollutants, plastics, and harmful chemicals.
Stay hydrated and maintain a balanced daily routine.
These simple lifestyle practices work together to support healthier metabolism, immune function, and overall well-being.
Why Epigenetics Matters
Epigenetics offers an empowering message. Your family history may influence your health, but it does not completely determine your future.
While genetics provides the foundation, your everyday decisions influence how your body uses that genetic information. Healthy nutrition, physical activity, quality sleep, stress management, and other positive habits create conditions that support healthier gene expression.
As scientific understanding continues to grow, epigenetics reminds us that consistent lifestyle choices can play an important role in maintaining long-term health and reducing the risk of many chronic conditions.
Read more on this blog Can Your Genes Heal? The Surprising Role of Epigenetics
pigenetics shows how lifestyle choices like fasting, quality sleep, and plant-based foods can influence your DNA expression and support long
