Exploring the Epigenetic Paradigm Shift

John J. Miller, MD

Psychiatric Times, Vol 38, Issue 6,

Early-life stress can modify an individual's genetic code, leading to mental health problems later in life. But by understanding the science of epigenetics, psychiatrists can treat these conditions, and prevent intergenerational trauma.


In the May 2021 issue of Nature Neuroscience, a research team at Icahn School of Medicine at Mount Sinai Health System in New York City made a fascinating discovery: Early life stress in mice resulted in an epigenetic modification of methyl groups on histone-3 in neurons in the nucleus accumbens, which in turn led to a lifelong increase in the mice’s vulnerability to stress. The team then demonstrated that treating the mice during exposure to early life stress with pinometostat, a drug currently in clinical trials to treat acute myeloid leukemia in humans, inhibited the enzyme responsible for this epigenetic methylation modification and decreased the effect of early-life stress exposure on stress later in life.1

This study is but one of a growing number of publications demonstrating the essential role of epigenetics in animal development, health, and disease. Without much fanfare, our understanding of epigenetics has been a significant paradigm shifter. Before we explore epigenetics, we need to review the foundational field of genetics.

Genetics 101

The 3 billion base pairs that constitute the human genome is the sequence of covalently bonded nucleic acids—adenine (A), thymine (T), cytosine (C), and guanine (G)—that form the double helix of DNA. This sequence forms the basis of the field of genetics and is created when the sperm joins the egg to form a zygote, which will contain this unique DNA sequence that remains constant throughout our life. In the case of identical twins, 100% of this DNA sequence is exactly the same, as both twins derive from the same zygote. With fraternal twins, 2 different sperm fertilize 2 different eggs to create 2 unique zygotes that have DNA sequences as different as 2 siblings with the same parents.

Let’s look at the genetic risk of schizophrenia, for example. In the general population, the risk of developing schizophrenia is about 1%, but if your identical twin develops schizophrenia, your risk increases to 50% due to the identical shared genome. In fraternal twins, the risk drops to roughly 16%, and in siblings it further drops to 9%. This demonstrates the role genetics plays on increasing or decreasing a person’s risk for various medical conditions. Significantly, the identical twin also has a 50% likelihood of not developing schizophrenia, which is attributed to numerous nongenetic factors. One of these factors is the individual’s epigenome, which can be different than the epigenome of their twin.2

In 2001, the Human Genome Project (an international consortium of research labs spearheaded by the US National Institutes of Health) and Celera Genomics (a private research company) announced they had independently completed a first draft of the sequencing of the human genome’s 3 billion base pairs. By 2003, the final draft was complete. Speculation by scientists, world leaders, and the media projected that, over the next decade, science and medicine would discover the genetic basis to many human diseases and disorders, with associated novel treatments. The complete sequencing of the human genome was an incredible achievement that continues to advance our understanding of the role of genes on health and disease. However, 20 years later it is disappointing to see how few actionable treatments have been developed. So, what’s next?

The Epigenome

The foundation of the epigenome involves covalent changes on certain areas of our chromosomes that will either increase or decrease the amount of activity at genes, hence impacting which gene products will be made in each particular cell. Think of the epigenetic processes like the software that determines which programs on a computer’s hard drive (the DNA genome) will be opened in RAM (in our analogy the genes that are ultimately expressed, creating our phenotype). The zygote has access to 100% of the genome. As embryological development occurs, cells begin to specialize and only require a small subset of the 20,000 or so protein coding genes that are available. One line of cells will begin to only produce proteins necessary for skin, while another set of cells will produce proteins for muscle, and yet another for neurons. This is an energy efficient process.

There are 2 basic ways that the chromosomal DNA/histone complex can be covalently modified to decrease or increase gene expression: methylation of the gene, or adding chemical tags to histones (the proteins around which the DNA is wrapped).3 In humans, the part of the gene that is methylated is the “promoter sequence,” a specific sequence of nucleotides, including a large density of CpG sites, which serve as a beacon and landing pad for the proteins that will then transcribe the messenger RNA (mRNA). mRNA will ultimately code for the gene’s protein. The more methyl groups attached to the promoter sequence, the less gene product will be synthesized. In specialized cells, the unneeded genes are heavily methylated and buried deep in the histones, likely never to be transcribed again.

The 3-dimensional shape of a histone can vary depending on chemical groups that can be covalently added depending on the degree of access needed to the gene associated with a particular histone. There are many chemical tags for histones, but the 2 best understood are methyl groups, which generally help the histone fold to hide the gene; and acetyl groups, which generally help the histone open up and make the gene more accessible.

There are enzymes that exist with job descriptions to either add or remove these methyl groups or acetyl groups to gene promoter sequences or histones, which in turn will be induced or repressed depending on the organism’s environment. At any given moment in time, an individual’s epigenome is unique and reflects the infinite number of events that determine what genes are turned on, or off, or somewhere in the middle.

Remember those identical twins that share 100% of the same DNA sequence? Epigenetic processes are already at work creating different expressions of this identical genome as soon as the shared zygote splits in 2 to create the twins.

Epigenetics at Work

As Nessa Carey, PhD, explains in The Epigenetics Revolution, baby rats respond to stress differently (throughout their lives) depending on how much grooming and licking they receive from their mother in the first week of their life.4 Some mother rats provide abundant grooming and licking to their babies, while other mother rats are less interactive with their babies, paying less attention with significantly less grooming and licking. Research found that the baby rats that received plenty of grooming and licking during that first week of life remained notably calm when exposed to stressful situations as adults. Meanwhile, the baby rats deprived of their mother’s attention during the first week of life responded with distress when exposed to the same stressful situations as adults.

The researchers then swapped the baby rats at birth: Babies of low grooming/licking mothers were switched to mothers that were high groomers/lickers, and vice versa. Remarkably, the first week of life for the baby rats was the determining factor for stress response as adults, rather than any inheritance from their biological mother. In addition, the stress-tolerant adult rats had lower levels of cortisol, adrenocorticotrophic hormone, and corticotrophin-releasing hormone than the adult rats that were neglected during that first week of life. Further research demonstrated that the stress-tolerant adult rats had decreased methylation of their cortisol receptor gene, in contrast to the neglected rats. Hence, that initial increased grooming created an epigenetic change that resulted in a lifelong increased expression of the cortisol receptor, creating greater resilience to stress.

The Dutch Hunger Winter

Can epigenetic modifications that occur during a person’s life be passed on to their offspring and future generations? From November 1944 through the spring of 1945 of World War II, the Germans, who controlled the Western Netherlands, set up a blockade that created a scarcity of food and severe starvation. From the detailed historical health care records, we have been able to study the long-term effects of the famine. Babies born to women who experienced starvation for the first 3 months of pregnancy and then resumed a normal diet when the blockade ended and food was available were likely to have a normal body weight at birth. However, babies born to women who were 6 months pregnant when the famine began were more likely to be underweight at birth.

These babies were followed by the health care system for decades. Remarkably, researchers discovered that the low-birth-weight babies continued to have body weights below average throughout their lives, including decreased rates of obesity as compared to the general population. The babies whose mothers experienced starvation during the first trimester of their pregnancy and had normal body weights at birth, had higher rates of obesity as compared to the general population decades later. Moreover, the grandchildren of the women who were starved during their first trimester also demonstrated some similar effects, suggesting a transgenerational inheritance.

One current hypothesis is that epigenetic changes to genes associated with nutrition and metabolism in the fetus would occur during a state of starvation to maximize the utilization of each calorie available. Significant epigenetic processes are in play during the first 3 months of fetal development, and these epigenetic modifications can then persist throughout life. Subsequent studies have shown that DNA methylation patterns in survivors of the Dutch Hunger Winter have demonstrated epigenetic modifications at genes involved in metabolism. The tragic circumstances of the Dutch Hunger Winter have provided a rare opportunity to study the potential effects of epigenetic changes early in life being passed on to future offspring. This is just one study; there is a growing literature in support of transgenerational epigenetic inheritance.

Epigenetics Today

A literature search for epigenetics in the National Library of Medicine generated 107,287 results, and 105,343 of these were published since the year 2000, demonstrating the explosion in this field over the past 2 decades.5

Epigenetic modifications sculpt an individual’s phenotype throughout their life.6 Epigenetic processes are most active, ubiquitous, and consequential throughout fetal development, as well as during the first 2 decades of life.

Returning to our identical twins, epigenetic differences are evident at birth, and these differences increasingly diverge throughout the twins’ lives. Research abounds comparing epigenetic profiles of individuals with and without a specific disease state to better understand the role of epigenetics in contributing to disease processes.

One significant consequence of the epigenetic contribution to phenotype is our growing understanding that genes that code for cytochrome P450 (CYP450) metabolic enzymes can be silenced or amplified, rendering the genotype of an individual’s CYP450 pharmacogenomic profile incomplete and unreliable. A recent study of CYP450 2E1 has demonstrated this phenomenon.7 This growing understanding of the epigenetic effects on CYP450 gene expression calls into question the reliability of pharmacogenomic testing that reports a genotype, but does not factor in the epigenetic phenotype that ultimately will determine CYP450 metabolic enzyme activity.

Epigenetics has provided fertile ground to understand how early life experience can directly increase or decrease the risk and severity of psychiatric disorders such as schizophrenia, bipolar disorder, and posttraumatic stress disorder.8

Concluding Thoughts

The epigenetic paradigm shift has received relatively little attention compared to the human genome sequencing, despite the broad and significant impact it has had on our understanding of how environmental factors during a single lifetime can covalently regulate which genes are expressed, and to what degree, from the fixed human genotype. In fact, it is the epigenome that ultimately determines the individual’s phenotype for increasing or decreasing the risk of various diseases and the functioning of metabolic and aging processes.9,10

In the field of oncology, drugs that treat some cancers by epigenetic mechanisms are already FDA approved and in clinical use. Azacitidine and decitabine are both inhibitors of DNA Methyltransferase-1 and are approved for myelodysplastic syndrome—a disease of the bone marrow. Vorinostat and romidepsin both inhibit a histone deacetylase and are approved for the treatment of refractory cutaneous T-cell lymphoma. Time will tell if epigenetic modifying drugs will become part of our treatment arsenal in psychiatry.

In this issue we are delighted to present 2 important articles by Bursztajn et al expanding on the field of epigenetics. Their first article, “Harnessing Epigenetic Knowledge to Promote Resilience while Avoiding the Historical Pitfalls of Genetic and Social Reductionism,” provides a historical overview of the field of epigenetics, as well as offering some philosophical reflections. Their second article, “Transgenerational Transmission of Resilience After Catastrophic Trauma,” our featured CME article, explores the rapidly evolving understanding of the potential epigenetic role on resilience after severe trauma, and how this resilience may be passed along to the traumatized individual’s offspring.

Dr Miller is Medical Director, Brain Health, Exeter, NH; Editor in Chief, Psychiatric Times; Staff Psychiatrist, Seacoast Mental Health Center, Exeter, NH; Consulting Psychiatrist, Exeter Hospital, Exeter, NH; Consulting Psychiatrist, Insight Meditation Society, Barre, MA.


1. Kronman H, Torres-Berrio A, Sidoli S, et al. Long-term behavioral and cell-type-specific molecular effects of early life stress are mediated by H3K79me2 dynamics in medium spiny neurons. Nat Neurosci. 2021;24(5):667-676.

2. Dempster EL, Pidsley R, Schalkwyk LC, et al. Disease-associated epigenetic changes in monozygotic twins discordant for schizophrenia and bipolar disorder. Human Molecular Genetics. 2011;20(24):4786-4796.

3. Kular L, Kular S. Epigenetics applied to psychiatry: Clinical opportunities and future challenges. Psychiatry Clin Neurosci. 2018;72(4):195-211.

4. Carey N. The Epigenetics Revolution. Columbia University Press; 2012.

5. PubMed.gov. Accessed May 8, 2021.

6. Kanherkar RR, Bhatia-Dey N, Csoka AB. Epigenetics across the human lifespan. Front Cell Dev Biol. 2014;2:49.

7. Kronfol MM, Jahr FM, Dozmorov MG, et al. DNA methylation and histone acetylation changes to cytochrome P450 2E1 regulation in normal aging and impact on rates of drug metabolism in the liver. Geroscience. 2020;42(3):819-832.

8. Blacker CJ, Frye MA, Morava E, et al. A review of epigenetics of PTSD in comorbid psychiatric conditions. Genes. 2019;10(2):140.

9. Mazzone R, Zwergel C, Artico M, et al. The emerging role of epigenetics in human autoimmune disorders. Clin Epigenetics. 2019;11(1):34.

10. Ling C, Ronn T. Epigenetics in human obesity and type 2 diabetes. Cell Metab. 2019;29(5):1028-1044. ❒

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