A recent study linked adolescent alcoholism to brain disorders later in adult life. Bohnsack et al. (2022), reporting in Science this month, claim that heavy drinking in adolescence impacts the amygdala, which is part of the brain’s temporal lobe involved in managing memory and emotions .
By conducting experiments on mice and supplementing information from humans, scientists found that drinking alcohol between the ages of 18 and 25 led to a reduction in the production of activity-regulated cytoskeletal protein (ARC)which plays a key role in creating and consolidating memories.
This is done via an “epigenetic” deletion of synaptic activity response element (SARE), a region of DNA close to the genetic code responsible for the production of ARC. Epigenetic phenomena are those where the environment in which an individual grows and lives, as well as his behavior, affects the behavior of genes.
There is, however, no change in the actual DNA sequence, but in the structure of chromatin – a complex of DNA and proteins – which packs DNA tightly inside the nucleus. In particular, chromatin contains many nucleosomes, which are DNA wrapped around 8 histone proteins, like a thread around a bobbin. But is there a clear link between alcohol consumption and changes in the histone protein that suppress the production of the ARC protein?
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In order to establish a relationship between the environment/behaviour and the SARE site, Bohnsack et al. 2022 used CRISPR-dCas9, a tool used for epigenetic modifications, to modify histone proteins. The dCas9 protein was attached to P300, a histone protein that promotes RNA production (the RNA is then converted into protein), and targeted to the SARE site. Next, the SARE site was targeted by dCas9 attached to KRAB, a protein that suppresses RNA copying.
“These new and rapidly evolving tools make it possible to selectively modify the epigenome at a single genomic locus and to study downstream effects at the molecular, cellular, circuitry and behavioral levels,” say the study authors. These experiments were conducted on a group of mice with unlimited access to food and water; and the targeted tissue region was the central core of the amygdala.
The study revealed that when the site is targeted by the dCas9-P300 complex, the expression of ARC increases. When the site is targeted by the dCas9-KRAB complex, the expression of ARC decreases. Therefore, one thing is clear, that epigenetic remodeling of SARE alone is able to flip ARC expression in both directions.
Bohnsack et al. (2022) also demonstrate that not only rodents that consume alcohol in adolescence exhibit anxiety-like behaviors, but also increased alcohol consumption in adulthood. SARE epigenetic mutations capable of recovering lost ARC expression (due to alcohol consumption) resulted in decreased alcohol dependence as well as decreased anxiety behaviors in adulthood. SARE mutations that further reduced ARC expression (here, dCas9-KRAB) only served to exacerbate alcohol dependence and anxiety in adulthood. This result, according to the authors, establishes a strong link between alcohol consumption in adolescence and its consequence on the ARC gene.
The research also describes the mechanism by which epigenetic remodeling of SARE regulates the expression of a gene that is nearly 7000 base pairs long (base pair is the unit by which the length of a DNA sequence or RNA is measured) away from it. This mechanism is known as “chromatin looping”. Here, elements that are seemingly far apart in terms of base pair measurements are quite close to the genetic sequence that is directly responsible for producing a certain protein. Bohnsack et al. (2022) further confirm that when the SARE site is targeted by dCas9-P300 (the promoter histone protein), it enhances the formation of these chromatin loops.
The discovery has enormous potential in the use of epigenetic tools to reverse SARE site deletion and ultimately increase the effects of alcohol consumption in adolescents. But the road is not so straightforward, the authors note, because these epigenetic tools have diverse functions – other than just modifications at the SARE site – that are not yet fully understood.
The author is a researcher at the Indian Institute of Science (IISc) in Bengaluru and a freelance science communicator. He tweets at @critvik.
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