Researchers identify epigenetic mechanisms responsible for longevity stress susceptibility

Epigenetic alterations that occur in a major cell type in the brain’s circulatory system control how early life stress increases susceptibility to excess weight in adulthood, researchers at Icahn School of Medicine at Mount Sinai has learned. In a study in Ignorance of nature, the team also reported that a low-molecular protector of the enzyme responsible for this mutation, which is currently being developed as an anti-cancer drug, has the potential to increase its vulnerability. in terms of longevity stress in reversing animal models.

It has long been known that lifelong stress exposures control lifelong exposure to subsequent stress. Here we found a major molecular mechanism that mediates the lasting effects of that stress. By doing this, we created an action biological target for the treatment of early stress-induced vulnerabilities, which could open the door to potential clinical studies on the target. this medication to control stress-related depression disorders. “

Hope Kronman, MD, lead author, PhD student in Nash Department of Family Neonatology and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai

The lifelong history of stress is the most well-known risk factor for depression in humans. Previous studies have shown that early life stress increases the risk of adult depression by as much as three times, depending on the time, intensity and specific features. Early life stress is also known to increase the likelihood of weight-bearing behavior later in life, and to have particularly strong effects on the nucleus accumbens, an essential part of the brain’s reward system.

The Mount Sinai study focused on epigenetic changes within cells; these are chemical changes in gene activity that are not caused by our DNA code, but by molecules that control when, where, and to what extent our genetic material is activated. Researchers identified previously unknown epigenetic mechanisms that mediate the lasting effects of early-life stress; a device called H3K79me2 (Lysine 79 demethylation of Histone H3) -; in the nucleus accumbens. Early life stress induces this approach selectively in the medial spike D2 neurons of the nucleus accumbens and thus reprogramming the cells to be more vulnerable to the second event of stress as an adult. .

The discovery of this mechanism led to neutral approaches in asking what epigenetic change-; out of hundreds -; which is more prone to the effects of early life stress in the nucleus accumbens. The researchers used a technique called proteomics to reveal that H3K79me2 is the most epigenetic change regulated by early life stress in this brain region and, at the same time, used RNA sequences to show that it is DOT1L the most regulated epigenetic enzyme, which catalyzes H3K79me2.

The importance of using a neutral or open approach to identifying critical approaches to disease pathophysiology was emphasized by the study’s lead author, Eric J. Nestler, MD, PhD, Director of the Friedman Brain Institute and Professor of Family Neuroscience Nash at the Icahn School of Medicine at Mount Sinai. “Through this approach we were able to discover the crucial role that this same type of histone conversion out of hundreds plays in centralizing the ability of weight early in our lives to be more prone. stress and depression over a lifetime. “

Dr. Nestler and his team also showed that manipulation of the DOT1L enzyme in median D2-mediated neurons of the nucleus accumbens bilaterally controls stress vulnerability. That is, an increase in DOT1L in this cell type increases stress susceptibility in animal models, while a decrease in DOT1L exerts the opposite effect. “Through the use of RNA sequences we then showed that overexpression of DOT1L significantly replicates the gene expression changes resulting from early life stress, whereas overexpression of DOT1L significantly impairs early life stress potential. to effect gene expression changes, ”Dr. Nestler explained.

This study set the platform for researchers to test the effect of a selective, small-molecule inhibitor of DOT1L, pinometostat, now in advanced clinical trials for the treatment of acute myeloid leukemia. In the first study of the drug’s effect on neuropsychiatric disease models, the Mount Sinai team found that twice-daily injection of the inhibitor neglected the effects of early-life stress vulnerability on adult animals, without extracting visible side effects.

“We are very encouraged by these decisions which support the potential use of the designated early life pressure device for medical purposes,” said Dr. Kronman. They reveal a fundamentally new pathway for developing improved therapies for depression, which is urgently needed as more than a third of people with this syndrome are appropriately treated by depression. conventional medicine. “