Unraveling the epigenetic landscape of depression: focus on early life stress

Abstract

Depression is a devastating psychiatric disorder caused by a combination of genetic predisposition and life events, mainly exposure to stress. Early life stress (ELS) in particular is known to “scar” the brain, leading to an increased susceptibility to developing depression later in life via epigenetic mechanisms. Epigenetic processes lead to changes in gene expression that are not due to changes in DNA sequence, but achieved via modulation of chromatin modifications, DNA methylation, and noncoding RNAs. Here we review common epigenetic mechanisms including the enzymes that take part in reading, writing, and erasing specific epigenetic marks. We then describe recent developments in understanding how ELS leads to changes in the epigenome that are manifested in increased susceptibility to depression-like abnormalities in animal models. We conclude with highlighting the need for future studies that will potentially enable the utilisation of the understanding of epigenetic changes linked to ELS for the development of much-needed novel therapeutic strategies and biomarker discovery.

Transcriptomic signature of early life stress in male rat prefrontal cortex

“…Here we carried out a genome-wide analysis of gene expression changes in response to ELS induced by LN in male rat PFC and identified a PFC-specific gene expression signature that is robust across rodent species and ELS paradigms. Accumulating evidence from multiple rodent models of ELS supports the notion that behavioural phenotypes induced by ELS are associated with epigenomic changes, which in turn leads to changes in gene expression ( Torres-Berrío et al, 2019 ). Most of these data come from studies of hippocampus, amygdala, and the VTA (reviewed in ( Torres-Berrío et al, 2019 )).…”

The Importance of Epigenetics in Diagnostics and Treatment of Major Depressive Disorder

“…Interestingly, a significant part of known lncRNAs has been found to be expressed in brain tissue [ 197 , 198 ]. There are many described lncRNAs ( Table 6 ) that are involved in different stages of brain development and its activity.…”

Resilience: Safety in the Aftermath of Traumatic Stressor Experiences

“…Significantly, the proactive effects of stressors in relation to neurotrophins, inflammatory mechanisms, and gut microbiota were particularly prominent if they had been experienced during early life (Burns et al, 2018 ; Audet, 2019 ). Such outcomes may reflect the sensitization of neurochemical systems, or the introduction of epigenetic changes that manifested as altered responses to later challenges (Szyf, 2011 ; Torres-Berrío et al, 2019 ). Further to this, stressors over the lifetime can have cumulative actions that favor the development of pathological outcomes, more so if the actions of stressors had been “embedded” during childhood through epigenetic changes and then exacerbated by further stressor encounters (Szyf, 2019 ).…”

“…These actions are further affected by the type and timing of stressor challenges (Burns et al, 2018;Torres-Berrío et al, 2019). However, there are so many experiential and biological (hormonal, neurochemical, growth factor, and inflammatory) changes associated with stressful events that it may be impractical to assign a given process to any particular pathology.…”

“…Likewise, genetic and epigenetic factors that code for particular biological features (e.g., processes related to glucocorticoid or neurotrophin functioning) are tied to the occurrence of behavioral and physical disturbances (Suri et al, 2013 ; Szyf et al, 2016 ; Mehta et al, 2020 ), and glucocorticoids influence epigenetic responses to stress (Reul et al, 2014 ). These actions are further affected by the type and timing of stressor challenges (Burns et al, 2018 ; Torres-Berrío et al, 2019 ). However, there are so many experiential and biological (hormonal, neurochemical, growth factor, and inflammatory) changes associated with stressful events that it may be impractical to assign a given process to any particular pathology.…”