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Findings by Icahn School of Medicine at Mount Sinai researchers suggest that an epigenetic change in a major cell type in the brain’s reward circuitry controls how stress during early life increases susceptibility to additional stress in adulthood. Their studies, in mice, also showed that a clinical-stage small molecule anticancer candidate, pinometostat—which acts to inhibit the enzyme responsible for the observed modification—was able to reverse increased vulnerability to lifelong stress in animal models.

“It has long been known that stress exposures throughout life control lifelong susceptibility to subsequent stress,” stated Hope Kronman, an M.D., Ph.D. student in the Nash Family Department of Neuroscience and The Friedman Brain Institute, Icahn School of Medicine at Mount Sinai. “Here we discovered a key molecular mechanism that mediates the lasting effects of that stress. In so doing, we generated an actionable biological target for treating early-life stress-induced susceptibility, which could open the door to potential clinical investigations of this pharmacological target for controlling stress-associated depressive disorders.” Kronman is lead author of the team’s published paper in Nature Neuroscience, which is titled, “Long-term behavioral and cell-type-specific molecular effects of early life stress are mediated by H3K79me2 dynamics in medium spiny neurons.”

A lifelong history of stress is the strongest known risk factor for depression in humans. Previous studies have shown that early-life stress (ELS) increases the risk of adult depression as much as threefold, depending on its timing, intensity, and specific features. Early-life stress is also known to increase the likelihood of behavioral susceptibility to stress later in life, and to have particularly strong effects on the nucleus accumbens, (NAc) an essential component of the brain’s reward system. “Importantly, ELS has been shown to increase the likelihood of behavioral susceptibility to stress later in life, with particularly strong effects in the NAc, at the transcriptional and physiological levels,” they wrote. “As such, it plays an important role in gating the effects of stress on depression-related behavioral abnormalities.”

To better understand how ELS alters transcription in the NAc to increase susceptibility to depression in adulthood, the scientists turned to a mouse model of ELS during a specific period in pre-weaning development. “This procedure does not cause life-long behavioral abnormalities on its own but increases susceptibility to a second hit of stress later in life,” they wrote.

The team focused on epigenetic modifications within cells, effectively chemical changes in the activity of genes that are not triggered by our inherited DNA code, but by molecules that regulate when, where, and to what degree our genetic material is activated. “… we examined chromatin modifications, which have the power to prime gene expression changes long after an initial insult, using mass spectrometry (MS) on adult NAc tissue of post-ELS male and female mice.”

Their studies identified a previously unknown epigenetic mechanism, known as H3K79me2 (demethylation of Lysine 79 of Histone H3), in the nucleus accumbens, which appears to mediate the lasting effects of early-life stress. Their studies found that early-life stress induces this mechanism selectively in D2-type medium spiny neurons of the nucleus accumbens, and thereby reprograms the cells to increase vulnerability to a second episode of stress in adulthood.

The discovery of this mechanism involved unbiased approaches of inquiring which epigenetic modification – out of many hundreds – would be the most likely to mediate the effects of early-life stress in the nucleus accumbens. Using proteomics techniques revealed that H3K79me2 as the epigenetic modification most highly regulated by early-life stress in this brain region. In parallel, the researchers carried out RNA sequencing to show that the most highly regulated epigenetic enzyme is DOT1L, which is one of the enzymes that controls the H3K79me2 modification. “Combined, these observations revealed the prominent and lasting regulation of H3K79 methylation, and transcription of its writer enzyme DOT1L, in the NAc after ELS,” they wrote.

Senior study author, Eric J. Nestler, M.D., Ph.D, director of The Friedman Brain Institute and Nash Family Professor of Neuroscience at the Icahn School of Medicine at Mount Sinai, emphasized the importance of using an unbiased or open-ended approach to identify crucial mechanisms of disease pathophysiology. “Through this approach we were able to uncover the essential role played by this one type of histone modification out of many hundreds in mediating the ability of stress early in life to increase susceptibility to stress and potentially depression over a lifetime.”

Nestler and his team further showed that stress susceptibility could be controlled by manipulating the enzyme DOT1L in D2 medium spiny neurons of the nucleus accumbens. They found that overexpressing DOT1L in this cell type increased stress vulnerability in animal models, while using a microRNA to decrease DOT1L had the opposite effect. “Knockdown of Dot1l in NAc D2 MSNs of adult mice that had experienced ELS reversed their ELS-induced behavioral susceptibility,” they wrote. “Conversely, Dot1l overexpression in NAc D2 MSNs of Std animals replicated the ELS-induced behavioral phenotype.”

Nestler further explained “Through the use of RNA sequencing we then demonstrated that DOT1L overexpression dramatically recapitulates the gene expression changes that occur from early life stress, whereas DOT1L knockdown dramatically blocks the ability of early life stress to produce gene expression changes.

The findings prompted the researchers to test the effects of a selective, small-molecule inhibitor of DOT1L, pinometostat, which is currently undergoing Phase II clinical trials for treating acute myeloid leukemia. Through an initial set of studies exploring the drug’s effect on neuropsychiatric disease models, the Mount Sinai team found that twice-daily injections of the DOT1L inhibitor reversed the susceptibility-priming effects of early life stress on adult male animals, without producing detectable side effects.

“… to our knowledge, our work represents the first exploration of the drug’s actions in neuropsychiatric disease” they noted. “… systemic delivery of a small molecule inhibitor of DOT1L reversed ELS-induced behavioral deficits, indicating the clinical relevance of this epigenetic mechanism … A 10-d, twice-daily course of injections— which decreased levels of H3K79me2 in NAc—was sufficient to reverse the behavioral effects of ELS on adult animals, without producing detectable side effects.”

The team acknowledged that their initial tests did not look at brain region or cell-type specificity of DOT1L–H3K79me2 actions, nor its use in females. However, they concluded, their experiment “… does support the possible viability of pursuing this novel ELS-induced epigenetic mechanism for therapeutic purposes.”

“We’re greatly encouraged by these findings which support the possible use of the novel early life stress mechanism we identified for therapeutic purposes,” said Kronman. “They reveal a fundamentally new pathway for the development of improved treatments for depression, which are urgently needed given that more than one-third of all individuals with this syndrome are inadequately treated with current therapeutics.”

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