Introduction
The adrenal glands secrete glucocorticoids, which are steroid hormones. As the byproducts of the hypothalamic-pituitary-adrenal (HPA) axis, which responds to stress, they are crucial for the maintenance of both basal and stress-related homeostasis. Glucocorticoids control a wide range of biological processes and have a significant impact on numerous physiologic processes. In the therapeutic care of numerous inflammatory, autoimmune, and lymphoproliferative illnesses, glucocorticoids are employed as powerful immunosuppressive agents in pharmacologic concentrations. The glucocorticoid receptor is an intracellular receptor protein that mediates the effects of glucocorticoids at the cellular level.
It is a member of the nuclear transactivating factor superfamily comprising steroid, sterol, thyroid, retinoid, and orphan receptors, which has over 200 members overall and over 40 currently cloned and described members in mammals. There are 777 amino acid residues in the human glucocorticoid receptor. Almost all human tissues and organs, including neural stem cells, express glucocorticoid receptors. Glucocorticoid receptor works as a hormone-dependent transcription factor that controls the expression of glucocorticoid-responsive genes, which presumably make about three to ten percent of the human genome and can be affected either directly or indirectly by the ligand-activated glucocorticoid receptor.
What Is a Glucocorticoid Receptor, and How Does It Work?
Cortisol and other glucocorticoids bind to the glucocorticoid receptor, also known as NR3C1 (nuclear receptor subfamily 3, group C, member 1). The glucocorticoid receptor regulates the genes that affect growth, metabolism, and immune response and is expressed in practically all body cells. The receptor gene has diverse (pleiotropic) effects in various areas of the body because it is produced in a variety of ways. The major mechanism of action of glucocorticoids when they bind to glucocorticoid receptors is the control of gene transcription. The cell's cytosol is home to the unbound receptor. The receptor-glucocorticoid complex can proceed in one of two ways after the glucocorticoid and receptor are bonded together.
In humans, the glucocorticoid receptor protein is encoded by the NR3C1 gene, which is located on cortisol and other glucocorticoids bind to the glucocorticoid receptor, also known as NR3C1 (nuclear receptor subfamily 3, group C, member 1).
The glucocorticoid receptor, which plays a significant role in the endocrine effect on the brain, specifically the stress response in central nervous system structures, is receiving attention as a novel marker of neuroendocrine integration. The receptor is currently thought to play a role in both short-term and long-term responses to stressors, and it may be essential to understanding psychological illnesses, including some or all subtypes of depression and post-traumatic stress disorder. Almost all body cells express the glucocorticoid receptor, which controls the genes that impact immune response, metabolism, and growth. The receptor gene is produced in various ways, resulting in several varied (pleiotropic) actions in various parts of the body. When glucocorticoids bind to the glucocorticoid receptors, their primary mechanism of action is the regulation of gene transcription. The unbound receptor resides in the cytoplasm of the cell.
What Is Epigenetics?
Epigenetic alterations to DNA control whether or not genes are activated. These alterations are connected to DNA and do not alter the order in which the DNA building blocks are arranged. The epigenome is all the modifications that control how genes are expressed inside a cell’s entire set of DNA (deoxyribonucleic acid), called the genome. Epigenetic modifications affect the synthesis of proteins in cells by influencing the decision of which genes are activated or inactive. Each cell only generates the proteins required for it to operate, owing to this control.
For instance, muscle cells do not create the proteins that support bone formation. Epigenetic alteration patterns range across individuals, between tissues within an individual, and even between individual cells within a tissue. The epigenome can be impacted by environmental factors like a person's nutrition and exposure to contaminants. When cells divide, epigenetic alterations can be preserved from cell to cell and, in some situations, passed down through the generations.
How Does the Dysregulation of Stress Hormone Alter the Epigenetic Glucocorticoid Receptor?
The epigenetic changes brought on by major life stressors are a significant factor that has been linked to the emergence of glucocorticoid receptor imbalance and hypothalamic-pituitary axis dysfunction. As the interface between the genome and the environment, epigenetics includes all the processes that affect gene expression without altering DNA sequences. These include three-dimensional modifications to chromatin conformation, non-coding RNAs, post-translational histone modifications, and DNA methylation. A memory system that transfers and maintains information about previously stressful experiences to progeny cells has been postulated. This memory system could influence how cells react to future stressor stimuli.
The action of glucocorticoid receptors has also been linked to the methylation of a number of genes; glucocorticoid receptors can induce histone modifications, such as methylation and acetylation of histone proteins, via direct glucocorticoid receptors binding or via interaction of glucocorticoid receptors with other transcription factors that recruit histone acetyltransferases. Glucocorticoid receptor signaling during stress has generally been associated with demethylation processes.
How Does Epigenetic Modulation of Glucocorticoid Receptors in Posttraumatic Stress Disorder Occur?
Some people with posttraumatic stress disorder have decreased basal salivary cortisol levels and increased glucocorticoid receptor sensitivity. Epigenetic processes may control how cortisol and glucocorticoid receptors operate, according to recent studies. In order to combine and cross-validate those results, researchers evaluate the levels of cortisol, glucocorticoid receptor expression, and promoter methylation in peripheral T cells between healthy controls and people who had been given a lifetime posttraumatic stress disorder diagnosis. Lifetime posttraumatic stress disorder sufferers release less cortisol in the morning, have higher levels of human glucocorticoid receptor total, 1B, and 1C mRNA expression, and have lower levels of overall methylation in the promoters of human glucocorticoid receptor 1B and 1C. The expression of human glucocorticoid receptor 1B mRNA and cortisol were inversely linked. In addition, the levels of human glucocorticoid receptor total and 1B mRNA expression were inversely linked with both overall and CpG site-specific methylation. In terms of cortisol, glucocorticoid receptor expression mRNA, or DNA methylation data, there was no difference between posttraumatic stress disorder that had already subsided and that had not. Traumatic events lead to transcriptional modifications that are associated with the hypoactive hypothalamus-pituitary-adrenal axis in people with posttraumatic stress disorder. Traumatic events also modify DNA methylation in specific human glucocorticoid receptor promoters.
Conclusion
Glucocorticoids are the main mediators of the epigenetic changes brought on by stress and their connection to the development of stress-related diseases. Strong evidence points to epigenetic changes in stress-related genes implicated in glucocorticoid signaling as a method by which stressful experiences are established in a person's biology. Epigenetic changes can affect how a person responds to stressors in the future and, when they are cumulative, can help people develop diseases connected to stress. According to a number of studies, epigenetic modifications can actually be passed down to the next generation, and as a result, stressful parental experiences may affect their children's susceptibility to various pathological illnesses.
