In earlier research, the UIC team found that alcohol abuse during adolescence altered brain chemistry in the enhancer region of Arc genes — activity-regulating cytoskeleton-associated protein immediacy genes — and reduced the expression of Arc in the amygdala of rodents and humans. expression in. This epigenetic reprogramming of the Arc gene in the emotional and memory centers of the brain contributes to susceptibility to anxiety and alcohol use disorders in adulthood.
In the new study, scientists show that this lifelong epigenetic reprogramming can actually be reversed by gene editing.
“Early alcohol abuse may have long-term and significant effects on the brain,” said study senior author Subhash Pandey, the Joseph-A-Flaherty Endowed Professor of Psychiatry and director of UIC’s Center for Alcohol Epigenetics Research. provides evidence that gene editing is a potential antidote to these effects, providing the brain with a ‘factory reset’ mode, if you will.”
Pandey and his team used a gene-editing tool called CRISPR-dCas9 in their experiments to manipulate the Arc gene’s histone acetylation and methylation processes in an adult rat model. These processes make it easier or harder for genes to be activated.
First, the researchers looked at intermittent alcohol exposure in adult rats during their adolescence, which is roughly equivalent to 10 to 18 years of age in humans. They observed that when dCas9 was used to promote acetylation, a process that loosens chromatin and allows transcription factors to bind to DNA, Arc gene expression normalized. Also, indicators of anxiety and alcohol consumption decreased.
Anxiety was measured by behavioral tests, such as by recording the exploratory activity of rats placed in a maze test, while alcohol preference was measured by monitoring rats’ choice between two bottles consisting of tap water, sugar water, and alcohol of varying concentrations (3). %, 7%, and 9%) are measured by the amount of fluid consumed.
In a second model, the researchers studied adult rats without early alcohol exposure. When inhibitory dCas9 was used to promote methylation, which tightened chromatin and prevented transcription factors from binding to DNA, Arc expression decreased and indicators of anxiety and alcohol consumption increased.
“These results suggest that epigenome editing in the amygdala can improve adult psychopathology following adolescent alcohol exposure,” the authors report.
“Adolescent alcohol abuse is a serious public health problem, and this research not only helps us better understand what happens in the developing brain when they are exposed to high levels of alcohol, but more importantly gives us hope that there are One day we will have effective treatments for the complex and multifaceted conditions of anxiety and alcohol use disorder,” said Pandey, who is also a Senior Research Career Scientist at Jesse Brown Veterans Medical Center. “The effect is bidirectional, validating the significance of Arc-enhancing genes in the amygdala in epigenetic reprogramming of adolescent alcoholism.”