Gestational and early postnatal adverse experiences, because of their psychopathological consequences later in life, represent a significant burden for the affected individual and society. We identified an epigenetic motif at over two thousand neuronal enhancers that, via dynamic switching between the active to inactive states, control gene expression. The stochastic balance between the two states is altered by early life adversity in a subpopulation of neurons, resulting in abnormal neuronal functioning. We will test the hypothesis that permanent changes in the methylation state of the identified enhancer ?switches? represent the ?cellular memory? of early life adverse experiences. Adversity-induced epigenetic changes increase the size and/or activity of neurons amenable for recruitment during behavioral tasks, that in turn, increase the responsiveness of the circuit to novel/stressful stimuli, manifested as exaggerated fear reaction/anxiety later in life. Besides of the theoretical implications (coding environmental effects via binary epigenetic switches), our work has translational significance. The sensitivity of DNA methylation based switches (due to their metastability), compared to the rest of the epigenetically more stable genome, provides an opportunity for their selective manipulation to mitigate the adverse effects of ELA.
Gestational and early postnatal adverse experiences often lead to maladaptive behaviors (such as anxiety and the inability to cope with stress) that represent a significant burden for the affected individual and society. We found that baseline behavioral responses to stress are controlled by gene regulatory epigenetic switches and that early life adversity alters the functioning of these switches, resulting in maladaptive behaviors. The epigenetic switches are highly malleable, compared to the rest of the epigenetically more stable genome, providing an opportunity for their selective manipulation by behavioral and pharmacological approaches to mitigate the adverse effects of early life adversity.
