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If DNA in each cell in human body is stretched end to end it is approximately 2 meters in length. This DNA has to be packed in the nucleus of a cell that is only 6 μm in diameter. Packaging DNA of this length into microscopic space of the nucleus understandably presents a serious challenge. This is however accomplished with the help of certain proteins on which the DNA is looped and folded thereby preventing it from getting tangled. These proteins are called histones and the DNA- protein complex together is referred to as chromatin. DNA sequence is wrapped around an octamer of histone proteins called nucleosomes. During this wrapping of DNA over the nucleosomes, there are certain regions of DNA that are readily accessible while there are other regions that are buried deep. Gene sequences present in DNA are expressed when these sequences undergo transcription to make RNA followed by translation to make proteins. Both these processes require various enzymes and proteins that can bind to DNA and subsequently to RNA catalyzing different steps. However, the binding of these entities to a particular gene sequence is dependent on whether that sequence lies in a region which is accessible or inaccessible on chromatin. The extent of packing of DNA over the nucleosomes determines its accessibility to these enzymes. While genes present in regions of DNA that is wound around relatively spaced nucleosomes is easily available for transcription, genes that are located in DNA wrapped over tightly packed nucleosomes is not readily accessed by the transcription machinery. Thus, gene sequences that are easily accessible are expressed while those that are densely packed or inaccessible are not expressed or are inactive and silent. The organization of DNA on nucleosomes can be modified, this changes the accessibility of genes as well. Modifications like acetylation and methylation of histone proteins can change the way these proteins interact with DNA resulting in changes in DNA packaging which in turn results in changes in gene expression.
Epigenetics refers to such modifications in chromatin structure that results in altered gene expression without any changes in DNA. Such modifications in nucleosome arrangement can be catalyzed by enzymes such as- histone acetyltransferases that add acetyl group and histone deacetylases (HDACs) that reverse the process, – histone methyltransferases (HMTs) that catalyze histone methylation and histone demethylases (HDMs) that remove it. A number of reports suggest remodeling of chromatin through above mechanisms throughout life. Even in monozygotic twins (similar genotype), diverse epigenetic patterns (methylation and acetylation) have been reported to result in different gene expressions. This difference at epigenetic level in individuals with same genetic background is possibly an effect of environment and individual life experiences. One of such external factors that has been reported to epigenetically modify expression of genes in limbic regions of brain is- stress.
Normal functioning of brain requires expression of diverse genes in a balanced and systematic manner. However epigenetic modifications such as acetylation and methylation can alter the way these genes express. A number of studies indicate role of such epigenetic modifications in pathogenesis of depressive disorders. Stress is one the most important environmental factor responsible for aberrant epigenetic processes. Animal studies report that early life stress such as abusive care or separation from mother can change epigenetic patterns in chromatin. The methylation patterns have been found to be altered in genes such as brain- derived nerve growth factor (BDNF), arginine vasopressin (Avp) and others that play important role in regulating hypothalamic-pituitary-adrenal (HPA) axis, which is primarily responsible for dealing with stress. On exposure to stress, a signaling cascade is initiated in hypothalamic-pituitary-adrenal (HPA) axis to prepare for “a fight or flight response”. This is initiated from hippocampus on release of chemicals like serotonin, dopamine and norepinephrine. Subsequently the hypothalamus synthesizes corticotrophin-releasing hormone (CRH), that can bind to anterior pituitary resulting in release of ACTH into circulation. ACTH in turn stimulates adrenal glands to produce and release glucocorticoids (GC). Glucocorticoids then act on peripheral organs to bring about different responses to stress. To reestablish normal conditions a feedback loop mechanism occurs in which GC bind to glucocorticoid receptors (GR) on hippocampus, hypothalamus and pituitary gland thus inhibiting the HPA axis. Early life stress has been found to have an effect on the levels of these receptors.
Experiments in rats show that the expression of glucocorticoid receptor (GR) is decreased in offspring of mothers that received low levels of maternal care / grooming. Additionally, the epigenetic patterns around GR gene were also contrasting in offspring that received high level to those that received low level of maternal care. Interestingly number and/or function of these receptors has also been reported to be reduced in case of depression.
Thus, early life stress in form of poor care, nutrition, loss etc can result in epigenetic modifications, such as in case of GR gene which in turn can have a likely impact on stress reactivity of HPA axis. A dysregulated HPA axis may lead to anxiety, depression and other neuropsychiatric disorders in adulthood.
In humans too, epigenetic modifications due to early life stress like low socioeconomic status has been reported in genes such as FKBP5, whose product regulates GR. The methylation patterns in genes associated with major depressive disorder (MDD) such as Morc1 are found to be different in children exposed to prenatal stress in comparison to those who are not. Additionally epigenetic changes in serotonin related genes due to early life experiences has also been reported to have an underlying effect on depression in later life.
Early life stressors such as lack of care & affection, loss of a near one, low nutrition, maltreatment, violence, war, natural disasters, dislocation etc have been associated with depression. A number of studies show that interaction of these stressors with genome results in epigenetic changes. Such epigenetic alterations in genes involved in HPA axis, can lead to development of depression and other mental disorders. Thus, there seems to be a relationship in stress driven epigenetic alterations and depression. Epigenetic changes in genes involved in glucocorticoid signaling (NR3C1, FKBP5), serotonergic (SLC6A4) signaling and neurotrophin (BDNF) have been shown to play important role in pathogenesis of depression.
Thus, an understanding of different stressors that result in epigenetic patterns associated with depression in early life, can enable us to understand its causes and in devising interventions that can reverse such epigenetic modifications and possible treatments. If left untreated mental difficulties in early life can become more serious as the child grows, hence a timely treatment is very crucial. Further providing a healthy environment for children in early life and avoiding such stressors is instrumental in lowering risk of development of depression in later life.