The modularity of current epigenetic editing technology allows us to evaluate the causality of connections from multiple angles. Now, epigenetic editing in rats using dCas9 activators and repressors has provided a welcome new perspective on how adolescent drinking can induce the onset of psychiatric conditions in adults.
Binge drinking during adolescence (a critical period for brain maturation) increases the risk of psychiatric disorders such as alcohol use disorder in adults and induces epigenetic reprogramming at an enhancer (the synaptic activity response element or SARE) associated with the immediate-early gene activity-regulated cytoskeleton-associated protein (Arc), which decreases Arc expression in a brain region known as the amygdala. These findings prompted researchers led by Subhash C. Pandey (University of Illinois at Chicago) to use dCas9-based epigenetic editing technology to determine whether chromatin remodeling of the Arc SARE in the amygdala causally impacts adult anxiety and alcohol use disorder.
Let´s hear how Bohnsack and colleagues answered this vexing question using epigenetic activators and repressors to uncover both sides of the mechanism:
- dCas9-P300 induces an increase in histone acetylation (H3K27ac) at the Arc SARE in the amygdala of rats exposed to binge levels of alcohol during adolescence (which induces heightened anxiety and increased alcohol consumption in adulthood) and recovers Arc expression to levels seen in alcohol-naïve control rats
- Permissive SARE chromatin remodeling supports dynamic chromatin looping (which initiates the deposition of permissive histone modifications at the Arc promoter) and increases enhancer RNA transcription (which prompts the removal of negative elongation factor [NELF – a transcriptional inhibitor] from the Arc promoter)
- The normalization of Arc expression levels through the activation of this epigenetic circuit attenuates adult rat anxiety to control levels and curbs excessive alcohol drinking
- On the flip side, dCas9-KRAB mediates increases in repressive histone methylation (H3K27me3) levels at the Arc SARE in the amygdala of alcohol-naïve control adult rats that foster a decrease in Arc expression
- Repressive SARE remodeling reduces enhancer RNA transcription and increases NELF promoter binding, while chromatin looping between the enhancer and promoter fails to exhibit any changes
- This repressive epigenetic remodeling event and associated reduction in Arc expression induces the onset of anxiety and alcohol drinking in adult alcohol-naïve control rats
Overall, these results provide robust evidence that epigenetic alterations at the Arc SARE in the amygdala induced by alcohol exposure during adolescence prompt the onset of psychiatric disorders as an adult; however, these findings also support the development of epigenetic editing as a possible therapeutic strategy.
For more on how an epigenetic editing strategy linked adolescent alcohol exposure to adult psychiatric disorders, see Science Advances, May 2022.