Consuming alcohol leads to epigenetic changes in brain memory centers
October 23, 2019
Science Daily/University of Pennsylvania School of Medicine
New research revealed a surprising pathway that shows alcohol byproducts travel to the brain to promote addiction memory. They show how acetate travels to the brain's learning system and directly alters proteins the regulate DNA function, impacting how some genes are expressed and ultimately affecting how mice behave when given environmental cues to consume alcohol.
Triggers in everyday life such as running into a former drinking buddy, walking by a once-familiar bar, and attending social gatherings can all cause recovering alcoholics to "fall off the wagon." About 40 to 60 percent of people who have gone through treatment for substance abuse will experience some kind of relapse, according to the National Institute on Drug Abuse. But what drives the biology behind these cravings has remained largely unknown.
Now, a team led by researchers from the Perelman School of Medicine at the University of Pennsylvania, have shown, in mouse models, how acetate -- a byproduct of the alcohol breakdown produced mostly in the liver -- travels to the brain's learning system and directly alters proteins that regulate DNA function. This impacts how some genes are expressed and ultimately affects how mice behave when given environmental cues to consume alcohol. Their findings were published today in Nature.
"It was a huge surprise to us that metabolized alcohol is directly used by the body to add chemicals called acetyl groups to the proteins that package DNA, called histones," said the study's senior author Shelley Berger, PhD, the Daniel S. Och University Professor in the departments Cell and Developmental Biology and Biology, and director of the Penn Epigenetics Institute. "To our knowledge, this data provides the first empirical evidence indicating that a portion of acetate derived from alcohol metabolism directly influences epigenetic regulation in the brain."
It has been known that a major source of acetate in the body comes from the breakdown of alcohol in the liver, which leads to rapidly increased blood acetate. In this study, the team, co-led by Philipp Mews, PhD, a former graduate student in the Berger lab who is now a postdoctoral fellow at Mount Sinai, and Gabor Egervari, MD, PhD, a postdoctoral fellow in Berger's lab, sought to determine whether acetate from alcohol breakdown contributes to rapid histone acetylation in the brain. They did so by using stable-isotope labeling of alcohol to show that alcohol metabolism does, in fact, contribute to this process by directly depositing acetyl groups onto histones via an enzyme called ACSS2.
Authors said that "ACSS2, 'fuels' a whole machinery of gene regulators 'on site' in the nucleus of nerve cells to turn on key memory genes that are important for learning. In fact, Berger and colleagues published findings on ACSS2 in a 2017 Nature paper. In that paper and previous work, the researchers found that ACSS2 is needed to form spatial memories.
In the current study, to better understand how the alcohol-induced changes in gene expression ultimately effect behavior, Berger and her team employed a behavioral test. Mice were exposed to "neutral" stimuli and alcohol reward in distinct compartments, distinguished by environmental cues. After this conditioning period, the researchers measured the preference of the mice by allowing them free access to either compartment, and recording the time spent in both the neutral and alcohol-paired chamber. They found that, as expected, mice with normal ACSS2 activity spent more time in the alcohol compartment following the training period.
To test the importance of ACSS2 in this behavior, researchers reduced the protein level of ACSS2 in a brain region important for learning and memory, and observed that, with lowered ACSS2, there was no preference shown for the alcohol-paired compartment.
"This indicates to us that that alcohol-related memory formation requires ACSS2," Egervari said. "Our molecular and behavioral data, when taken together, establish ACSS2 as a possible intervention target in alcohol use disorder -- in which memory of alcohol-associated environmental cues is a primary driver of craving and relapse even after protracted periods of abstinence."
Importantly, these findings suggest that other external or peripheral sources of physiological acetate -- primarily the gut microbiome -- may similarly affect central histone acetylation and brain function, which may either control or foster other metabolic syndromes.
In addition to investigating the impact of alcohol consumption on brain changes in adults, the team also looked into the effects of consumption in pregnant mice and thus the impact of alcohol on brain cells in developing mice. In utero, alcohol causes impaired neurodevelopmental gene expression and can elicit numerous alcohol-associated postnatal disease symptoms such as small head size, low body weight, and hyperactivity. And while the number of those affected by fetal alcohol spectrum disorders (FASDs) -- which includes fetal alcohol syndrome -- is unknown, the Centers for Disease Control and Prevention suggests that the full range of FASDs in the United States and some Western European countries could be as high as one to five percent of the population.
In this arm of the study, researchers found that, upon consumption of alcohol, acetate is delivered through the placenta and into the developing fetus. The fetal brains of these mice showed that alcohol exposure on the level of "binge drinking" in the pregnant female resulted in deposition of alcohol-derived acetyl-groups onto histones in fetal brains in early neural development in the mice.
Much like the primary results of the study being useful for the potential treatment of alcohol-use disorder, these results could have implications for understanding and combating fetal alcohol syndrome.
https://www.sciencedaily.com/releases/2019/10/191023132254.htm
A moderate dose of novel form of stress promotes longevity
July 10, 2019
Science Daily/Baylor College of Medicine
A newly described form of stress called chromatin architectural defect, or chromatin stress, triggers in cells a response that leads to a longer life. Researchers at Baylor College of Medicine and the Houston Methodist Research Institute report in the journal Science Advances that moderate chromatin stress levels set off a stress response in yeast, the tiny laboratory worm C. elegans, the fruit fly and mouse embryonic stem cells, and in yeast and C. elegans the response promotes longevity. The findings suggest that chromatin stress response and the longevity it mediates may be conserved in other organisms, opening the possibility of new ways to intervene in human aging and promote longevity.
"Chromatin stress refers to disruptions in the way DNA is packed within the nucleus of the cell," said corresponding author Dr. Weiwei Dang, assistant professor of molecular and human genetics and the Huffington Center on Aging and member of the Dan L Duncan Comprehensive Cancer Center at Baylor. "One of the factors that influences chromatin structure is proteins called histones."
In the nucleus of cells, DNA wraps itself around histone proteins forming a 'beads-on-a-string' structure called chromatin. Other proteins bind along chromatin and the structure folds further into more complicated configurations. Everything involving DNA would have to deal with this chromatin structure, Dang explained. For example, when a particular gene is expressed, certain enzymes interact with the chromatin structure to negotiate access to the gene and translate it into proteins. When chromatin stress happens, disruption of the chromatin structure can lead to unwanted changes in gene expression, such as expression of genes when they are not supposed to or lack of gene expression when it should occur.
In this study, Dang and his colleagues worked in the lab with the yeast Saccharomyces cerevisiae to investigate how the dosage of histone genes would affect longevity.
They expected that yeast genetically engineered to carry fewer copies of certain histone genes than normal or control yeast would have chromatin changes that would result in the yeast living less than controls.
"Unexpectedly, we found that yeast with fewer copies of histone genes lived longer than the controls," said first author Ruofan Yu, research assistant in molecular and human genetics in the Dang lab.
Yeast with a moderately low dose of histone genes showed a moderate reduction of histone gene expression and significant chromatin stress. Their response to chromatin disruption was changes in the activation of a number of genes that eventually promoted longevity.
In previous work Dang and colleagues had shown that in aging cells chromatin structure progressively falls apart. Histone alterations, such as a decrease in their protein levels, are a characteristic of the aging process, but the researchers showed that if they compensated for this age-related decrease in histone levels by overexpressing certain histone genes they extended the lifespan of aging yeast cells. In this study they discovered that moderately reducing the number of copies of histone genes in young yeast also promoted longevity.
"We have identified a previously unrecognized and unexpected form of stress that triggers a response that benefits the organism," Yu said. "The mechanism underlying the chromatin stress response generated by moderate reduction of histone dosage is different from the one triggered by histone overexpression we had previously described, as shown by their different profiles of protein expression responses."
Dang, Yu and their colleagues found that chromatin stress also occurs in other organisms such as the laboratory worm C. elegans, the fruit fly and mouse embryonic stem cells, and in yeast and C. elegans the chromatin stress response promotes longevity.
"Our findings suggest that the chromatin stress response may also be present in other organisms. If present in humans, it would offer new possibilities to intervene in the aging process," Dang said.
https://www.sciencedaily.com/releases/2019/07/190710193923.htm