A deeper understanding of the pathomechanisms leading to stress-related psychiatric disorders is important for the development of more efficient preventive and therapeutic strategies. Epidemiological ...studies indicate a combined contribution of genetic and environmental factors in the risk for disease. The environment, particularly early life severe stress or trauma, can lead to lifelong molecular changes in the form of epigenetic modifications that can set the organism off on trajectories to health or disease. Epigenetic modifications are capable of shaping and storing the molecular response of a cell to its environment as a function of genetic predisposition. This provides a potential mechanism for gene-environment interactions. Here, we review epigenetic mechanisms associated with the response to stress and trauma exposure and the development of stress-related psychiatric disorders. We also look at how they may contribute to our understanding of the combined effects of genetic and environmental factors in shaping disease risk.
Gene by environment interactions (G×E) shape the risk for psychiatric disorders. In this review, Klengel and Binder describe how underlying epigenetic mechanisms may contribute to G×E in stress-related psychiatric disorders and how this may influence future preventive and therapeutic strategies.
Summary FK506 binding protein 51 or FKBP5 is a co-chaperone of hsp90 which regulates glucocorticoid receptor (GR) sensitivity. When it is bound to the receptor complex, cortisol binds with lower ...affinity and nuclear translocation of the receptor is less efficient. FKBP5 mRNA and protein expression are induced by GR activation via intronic hormone response elements and this provides an ultra-short feedback loop for GR-sensitivity. Polymorphisms in the gene encoding this co-chaperone have been shown to associate with differential upregulation of FKBP5 following GR activation and differences in GR sensitivity and stress hormone system regulation. Alleles associated with enhanced expression of FKBP5 following GR activation, lead to an increased GR resistance and decreased efficiency of the negative feedback of the stress hormone axis in healthy controls. This results in a prolongation of stress hormone system activation following exposure to stress. This dysregulated stress response might be a risk factor for stress-related psychiatric disorders. In fact, the same alleles are over-represented in individuals with major depression, bipolar disorder and post-traumatic stress disorder. In addition, they are also associated with faster response to antidepressant treatment. FKBP5 might thus be an interesting therapeutic target for the prevention and treatment of stress-related psychiatric disorders.
Early life stress, such as childhood abuse, neglect and loss, is a well established major risk factor for developing depressive disorders later in life. We here summarize and discuss current ...developments in human research regarding the link between early life stress and depression. Specifically, we review the evidence for the existence of sensitive periods for the adverse effects of early life stress in humans. We further review the current state of knowledge regarding gene×environment (G×E) interactions in the effects of early life stress. While multiple genes operate in multiple environments to induce risk for depression after early life stress, these same genes also seem to enhance the beneficial effects of a positive early environment. Also, we discuss the epigenetic mechanisms that might underlie these G×E interactions. Finally, we discuss the potential importance of identifying sensitive time periods of opportunity, as well as G×E interactions and epigenetic mechanisms, for early interventions that might prevent or reverse the detrimental outcomes of early life stress and its transmission across generations.
Epidemiologic and genetic studies suggest common environmental and genetic risk factors for a number of psychiatric disorders, including depression, bipolar disorder, and schizophrenia. Genetic and ...environmental factors, especially adverse life events, not only have main effects on disease development but also may interact to shape risk and resilience. Such gene by adversity interactions have been described for FKBP5, an endogenous regulator of the stress-neuroendocrine system, conferring risk for a number of psychiatric disorders. In this review, we present a molecular and cellular model of the consequences of FKBP5 by early adversity interactions. We illustrate how altered genetic and epigenetic regulation of FKBP5 may contribute to disease risk by covering evidence from clinical and preclinical studies of FKBP5 dysregulation, known cell-type and tissue-type expression patterns of FKBP5 in humans and animals, and the role of FKBP5 as a stress-responsive molecular hub modulating many cellular pathways. FKBP5 presents the possibility to better understand the molecular and cellular factors contributing to a disease-relevant gene by environment interaction, with implications for the development of biomarkers and interventions for psychiatric disorders.
Exposure to early life stress (ELS), such as childhood abuse and neglect is a well established major risk factor for developing psychiatric and behavioral disorders later in life. Both prenatal and ...postnatal stressors have been shown to have a long-lasting impact on adult pathological states where the type and timing of the stressor are important factors to consider. There is a growing body of evidence suggesting that epigenetic mechanisms play a major role in the biological embedding of ELS. A number of studies now indicate that the epigenome is responsive to external environmental exposures, including the social environment, both during intra-uterine development and after birth. In this review, we summarize the evidence of long-lasting effects of ELS on mental health and behavior and highlight common and distinct epigenetic effects of stress exposure at different stages during development. These stages include postnatal stress, prenatal stress, i.e. in utero and stress occurring pre-conception, i.e. effects of stress exposure transmitted to the next generation. We also delineate the evidence for the possible molecular mechanisms involved in epigenetic programming by ELS and how these maybe distinct, according to the timing of the stress exposure.
Gene-by-environment interactions (G×Es) can provide important biological insights into psychiatric disorders and may consequently have direct clinical implications. In this review, we begin with an ...overview of the major challenges G×E studies have faced (e.g., difficulties replicating findings and high false discovery rates). In light of these challenges, this review focuses on describing examples in which we might begin to understand G×Es on the molecular, cellular, circuit, and behavioral level and link this interaction to altered risk for the development of psychiatric disorders. We also describe recent studies that utilize a polygenic approach to examine G×Es. Finally, we discuss how gaining a deeper understanding of G×Es may translate into a therapeutic practice with more targeted treatments.
Epigenetics and depression Penner-Goeke, Signe; Binder, Elisabeth B.
Dialogues in clinical neuroscience,
12/2019, Letnik:
21, Številka:
4
Journal Article
Odprti dostop
The risk for major depression is both genetically and environmentally determined.
It has been proposed that epigenetic mechanisms could mediate the lasting increases in
depression risk following ...exposure to adverse life events and provide a mechanistic
framework within which genetic and environmental factors can be integrated. Epigenetics
refers to processes affecting gene expression and translation that do not involve
changes in the DNA sequence and include DNA methylation (DNAm) and microRNAs (miRNAs) as
well as histone modifications. Here we review evidence for a role of epigenetics in the
pathogenesis of depression from studies investigating DNAm, miRNAs, and histone
modifications using different tissues and various experimental designs. From these
studies, a model emerges where underlying genetic and environmental risk factors, and
interactions between the two, could drive aberrant epigenetic mechanisms targeting
stress response pathways, neuronal plasticity, and other behaviorally relevant pathways
that have been implicated in major depression.
The link between dysregulated serotonergic activity and depression and anxiety disorders is well established, yet the molecular mechanisms underlying these psychopathologies are not fully understood. ...Here, we explore the role of microRNAs in regulating serotonergic (5HT) neuron activity. To this end, we determined the specific microRNA “fingerprint” of 5HT neurons and identified a strong microRNA-target interaction between microRNA 135 (miR135), and both serotonin transporter and serotonin receptor-1a transcripts. Intriguingly, miR135a levels were upregulated after administration of antidepressants. Genetically modified mouse models, expressing higher or lower levels of miR135, demonstrated major alterations in anxiety- and depression-like behaviors, 5HT levels, and behavioral response to antidepressant treatment. Finally, miR135a levels in blood and brain of depressed human patients were significantly lower. The current results suggest a potential role for miR135 as an endogenous antidepressant and provide a venue for potential treatment and insights into the onset, susceptibility, and heterogeneity of stress-related psychopathologies.
•miRs “fingerprint” of 5HT neurons position miR135 as potent regulator of 5HT system•miR135a levels are upregulated following 5HT-linked antidepressants treatment•miR135 levels in vivo influence behavior, 5HT levels, and antidepressant treatment•Lower levels of miR135a in blood and brain of depressed human patients
Issler et al. identify microRNA135 as potent regulator of serotonergic activity known to be associated with depression and anxiety disorders and suggest a role for miR135 as an endogenous antidepressant and provide a venue for potential treatment and insights into stress-related psychopathologies.
Stress responses and related outcomes vary markedly across individuals. Elucidating the molecular underpinnings of this variability is of great relevance for developing individualized prevention ...strategies and treatments for stress-related disorders. An important modulator of stress responses is the FK506-binding protein 51 (FKBP5/FKBP51). FKBP5 acts as a co-chaperone that modulates not only glucocorticoid receptor activity in response to stressors but also a multitude of other cellular processes in both the brain and periphery. Notably, the FKBP5 gene is regulated via complex interactions among environmental stressors, FKBP5 genetic variants, and epigenetic modifications of glucocorticoid-responsive genomic sites. These interactions can result in FKBP5 disinhibition that has been shown to contribute to a number of aberrant phenotypes in both rodents and humans. Consequently, FKBP5 blockade may hold promise as treatment intervention for stress-related disorders, and recently developed selective FKBP5 blockers show encouraging results in vitro and in rodent models. Although risk for stress-related disorders is conferred by multiple environmental and genetic factors, the findings related to FKBP5 illustrate how a deeper understanding of the molecular and systemic mechanisms underlying specific gene-environment interactions may provide insights into the pathogenesis of stress-related disorders.
PDF
