Epigenetics: The Biology of Psychological Change

Ida Pearl is a 16-year-old Caucasian female who has spent the past two months in bed due to the disability of chronic migraine. She is incapacitated by bright lights, loud noises, and the crowded halls of her high school. She has been prescribed multiple medications for chronic migraine without effect. Episodic migraine began with menses about four years ago. Attacks of migraine occurred once or twice a month and responded well to migraine-specific medication. The attacks became chronic on February 14 when her boyfriend broke up with her. There is no family history of migraine. Her parents are puzzled over what had happened.

The psychologist on the interdisciplinary team of a tertiary headache center met with Ida Pearl to learn the details of the breakup with her boyfriend. After establishing rapport and emphasizing the confidentiality of their exchange, the teenager confessed that she had been having dreams of her uncle, her father’s brother, sexually fondling her at age 12. She was afraid to tell her family for fear of their seeking revenge and she had no memory of the abuse. Could it be her imagination or a bad dream? The sexual contact with her boyfriend seemed to bring these upsetting memories into her awareness. When he broke up with her, she felt used, damaged, and dirty, like she did in her nightmares.

The psychologist asked the treatment team for support in recommending follow-up sessions with the therapist to work-through and counter the negative impact of the abuse on the adolescent’s behavioral response to stress. Until there is a resolution of the abuse issues that produce shame, chronic pain, and nightmares, there will likely be a continual lowering of the expression of glucocorticoid receptors, which has a knock-on effect on the hypothalamic-pituitary-adrenal (HPA) function. The subsequent over-activation of the HPA axis affects the ability to cope with stress, leaving affected individuals at risk of mood disorders and suicide.

Epigenetics

To understand Ida Pearl’s medical dilemma, it is essential to evaluate the role of epigenetics. Epigenetics is the study of how gene expression is controlled and orchestrated through the activation or deactivation of specific genes in response to environmental influences.[1]  In essence, it is how gene expression adapts to changes in diet, social and physical environments, and lifestyle choices.

In the 1940s, British embryologist Conrad Waddington used the term epigenetics to describe the interactions between genes and gene products, which direct development and give rise to an organism’s phenotype (observable characteristics).[2]  Since then, results of epigenetics studies have revolutionized the fields of genetics and developmental biology. Specifically, researchers have uncovered a range of possible chemical modifications to deoxyribonucleic acid (DNA) and to proteins called histones that associate tightly with DNA in the nucleus. These modifications can determine when or even if a given gene is expressed in a cell or organism.

Recent research has indicated that psychological trauma can leave epigenetic marks through a process called demethylation on DNA and genes that mediate the stress response.[3]  These results confirm that psychological trauma has a negative biological impact on the physiology’s ability to cope with stress.

Even though the genes inherited from parents remain constant throughout life, epigenetic changes such as DNA methylation can shape the effects on the individual. Epigenetic changes can be environmentally triggered and markedly affect development and behavior.  But, once identified, epigenetic marks are reversible.

Over 5 sessions with the psychologist, Ida Pearl confirmed that the sexual impropriety occurred. In a letter to her uncle that she later destroyed, she expressed her outrage over his taking advantage of her vulnerability which also created an emotional gulf between herself and her parents. She felt that somehow she was responsible for what had happened between her and her uncle and she questioned why her parents failed to protect her from him.

This trauma was stored away as a reminder never to be put into that situation again while at the same time, shame pushed the event out of her awareness. The resulting pain of this conflict was intensified and expressed in transformation of episodic into chronic migraine after what she perceived as betrayal by her boyfriend.

Over a period of three weeks, she followed a low carbohydrate diet, got out of bed every morning to photograph outdoor scenes around her home (her favorite form of recreation), photo-shopped the results, and kept a workbook of her daily progress in terms of regulating her finger temperature (into the 90’s for physiological re-calibration) and recording her comfort level (0 to 10). Hypersensitivity lessened as did the frequency of attacks of migraine. She was able to return to school during the fourth week.

Migraine is a complex disease with multiple gene expressions that produce a hyperexcitable nervous system. Epigenetics helps explain how environmental factors influence the expression of genomes through modulation of neuronal excitability. This notion of differential gene expression helps explain differences in migraine phenotypes, attack severity, and even pharmacological responsiveness. In addition, epigenetics emphasizes the importance of lifestyle, diet, and the physical environment on the progression or remission of migraine without the presence of mutations to individual genes implicated in maintaining neuronal homeostasis.

Epigenetic changes in humans, such as the effect of smoking on a developing embryo, have been found to be handed down to four (4) generations. In a species of fruit flies, Drosophila melanogaster, eye color changed from white to red by raising the surrounding temperature of the embryos in the first generation from 25 to 37 degrees Celsius. The flies later hatched with red eyes which continued in the following six generations even though the DNA sequence for the gene responsible for eye color remained the same for white-eyes.[4]

Epigenetics examines the inheritance of characteristics that are not set out in the DNA sequence. Epigenetic mechanisms form an additional, paramount level of information to the genetic information of DNA. This occurs through histones. At one time, considered a kind of packaging material for the DNA, in order to store DNA in an ordered and space-saving way, these proteins now have been shown to play additional roles. Depending on the chemical group they carry, if they are acetylated or methylated, they permanently activate or deactivate genes. New methods now allow researchers to show which genes have been activated or deactivated by the histones.

Cells Have a Memory [5]

Epigenetic marks, such as the modifications of the histones, are also important for the specialization of the body’s cells. They are preserved during cell division and are passed on to the daughter cells. If skin cells divide, more skin cells are created; liver cells form liver cells. In both cell types, all genes are deactivated except the ones needed by a skin or liver cell to be a skin or liver cell, and to function appropriately. The genetic information of the DNA is passed on along with the relevant epigenetic information for the respective cell type. It appears as if cells have a memory.

Another question remains for the inheritance of the epigenetic characteristics from parents to offspring. When the gametes are formed, certain epigenetic markers remain and are passed on to the offspring. The questions, which are currently being researched, are how much and which part of the epigenetic information is preserved and subsequently inherited?

Research is also looking at the influence of various substances from the environment on the epigenetic constitution of organisms, including humans. Diet and epigenetics appear to be closely linked. The most well-known example is that of the Agouti mice that are yellow, fat and are prone to diabetes and cancer. If Agouti females are fed supplemental vitamin B12, folic acid and cholin directly prior to and during pregnancy, they give birth to brown, slim and healthy offspring. They in turn have offspring similar to themselves.

Impact of Epigenetics on Biomedicine

As the mechanisms of epigenetics have become better understood, researchers have recognized that the epigenome—chemical modification at the level of the genome—also influences a wide range of biomedical conditions. This new perception has opened the door to a deeper understanding of normal and abnormal biological processes and has offered the possibility of novel interventions that might prevent or ameliorate certain diseases.

Certain tumors and cancers are believed to involve epigenetic changes attributable to environmental factors. These changes include a general decrease in methylation, which is thought to contribute to the increased expression of growth-promoting genes, punctuated by gene-specific increases in methylation that are thought to silence tumor-suppressor genes. Epigenetic signaling attributed to environmental factors has also been associated with some characteristics of aging by researchers that studied the apparently unequal aging rates in genetically identical twins.

One of the most promising areas of epigenetic investigation involves stem cells. Researchers have understood for some time that epigenetic mechanisms play a key role in defining the “potentiality” of stem cells. As those mechanisms become clearer, it may become possible to intervene and effectively alter the developmental state and even the tissue type of given cells. The implications of this work for future clinical regenerative intervention for conditions ranging from trauma to neurodegenerative disease are profound.

Researchers face the added challenge that epigenetic changes are transient by nature. That is, the epigenome changes more rapidly than the relatively fixed DNA code. An epigenetic change that was triggered by environmental conditions may be reversed when environmental conditions change again. Through epigenetic inheritance, some of the experiences of the parents may pass to future generations. At the same time, the epigenome remains flexible as environmental conditions continue to change. Epigenetic inheritance may allow an organism to continually adjust its gene expression to fit its environment – without changing its DNA code.

References

  1. Bird A. Perceptions of epigenetics. Nature. 2007 May 24;447(7143):396-398.
  2. Waddington, Conrad H. Organisers and Genes. Cambridge: Cambridge University Press, 1940.
  3. Klengel T, Mehta D, Anacker C, et al. Allele-specific FKBP5 DNA demethylation mediates gene-childhood trauma interactions. Nat Neurosci. 2013 Jan;16(1):33-41.
  4. ETH Zurich. “Epigenetics: DNA Isn’t Everything.” ScienceDaily. ScienceDaily, 13 April 2009. www.sciencedaily.com/releases/2009/04/090412081315.htm Accessed December 16, 2014.
  5. Web: Roadmap Epigenomics Project. http://www.roadmapepigenomics.org/