A recent study has established a connection between teenage alcoholism and brain disorders later in adult life. Bohnsack et al. (2022), reporting in Science this month, argue that excessive consumption of liquor during teenage impacts the amygdala, which is part of the temporal lobe of the brain that is involved with handling memory and emotions.
By conducting experiments on mice, and supplementing information from humans, scientists have found that alcohol consumption during the age of 18-25 leads to reduced production of activity regulated cytoskeletal (ARC) protein, which plays a key role in creating and consolidating memories.
This is done via an ‘epigenetic’ suppression of synaptic activity response element (SARE), a region of DNA that lies close to the genetic code that is responsible for producing ARC. Epigenetic phenomena are those where the environment in which an individual grows and lives, and his/her behaviour, affects the way genes behave.
There are, however, no changes in the actual DNA sequence, but in the structure of the chromatin – a complex of DNA and proteins – that packs DNA compactly inside the nucleus. In particular, chromatin contains many nucleosomes, which is DNA wrapped around 8 histone proteins, like a thread around a spool. But is there a clear link between alcohol consumption and modifications in the histone protein that suppress ARC protein production?
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In order to establish a relationship between environment/behaviour and the SARE site, Bohnsack et al. 2022 used CRISPR-dCas9, a tool to used to epigenetic modifications, to modify histone proteins. The dCas9 protein was tethered to P300, a histone protein that promotes production of RNA (RNA is then converted to protein), and targeted at the SARE site. Then, the SARE site was targeted by dCas9 tethered to KRAB, a protein that suppresses RNA copying.
‘These novel and rapidly evolving tools make it possible to selectively modify the epigenome at a single genomic locus and study the downstream effects at the molecular, cellular, circuit, and behavioural levels,’ authors of the study maintain. These experiments were conducted on a group of mice with unrestricted access to food and water; and the targeted tissue region was the central nucleus of the amygdala.
The study found that when the site is targeted by the dCas9-P300 complex, ARC expression increases. When the site is targeted by the dCas9-KRAB complex, the ARC expression decreases. Therefore, one thing is clear, that epigenetic remodelling of SARE alone is capable to tip ARC expression either way.
Bohnsack et al. (2022) also demonstrate that not only do rodents who consume alcohol during adolescence show anxiety-like behaviour, but also increased consumption of alcohol during adulthood. Epigenetic SARE mutations that were able to recover the lost ARC expression (due to alcohol consumption) led to a decreased alcohol dependence as well as decreased anxiety-like behaviour in adulthood. The 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 connection between alcohol consumption in adolescence and its consequence on ARC gene.
The research also delineates the mechanism by which the epigenetic remodelling of SARE regulates the expression of a gene that is nearly 7000 base-pairs (base pair is the unit by which the length of a DNA or RNA sequence is measured) away from it. This mechanism is known as ‘chromatin looping’. Here, elements that are apparently far off in terms of base-pair measurements come quite close to the genetic sequence that is directly responsible in producing a certain protein. Bohnsack et al. (2022) further confirm that when the SARE site is targeted by dCas9-P300 (the promoting histone protein), it enhances the formation of these chromatin loops.
The finding does hold tremendous potential in using epigenetic tools to reverse the suppression of the SARE site and, ultimately, augment the effects of teenage drinking. But the road is not that straightforward, authors note, for these epigenetic tools have diverse functions – other than just the modifications at the SARE site – that are not yet fully known.
The author is a research fellow at the Indian Institute of Science (IISc), Bengaluru, and a freelance science communicator. He tweets at @critvik.