Summary: Early-life stress triggers an epigenetic change in D2-type medium spiny neurons in the nucleus accumbens, increasing vulnerability to stress in adulthood.
Source: Mount Sinai Hospital
Researchers at the Icahn School of Medicine at Mount Sinai have identified a specific epigenetic mechanism in the brain’s reward circuitry that explains how stress experienced early in life raises the risk of heightened stress sensitivity later on.
Published in Nature Neuroscience, the study shows that a histone modification known as H3K79me2 is altered by early-life stress in the nucleus accumbens, a key node of the brain’s reward system. The team also demonstrated that inhibiting the enzyme that creates this modification can reverse the increased stress susceptibility in animal models.
“We have long known that stress across the lifespan shapes later vulnerability to stress,” says lead author Hope Kronman, MD, PhD student in the Nash Family Department of Neuroscience and The Friedman Brain Institute. “Our work identifies a concrete molecular pathway that carries the lasting imprint of early-life stress and points to a tractable biological target for intervention.”
Chronic or repeated stress across life is the strongest risk factor for depression. Previous research shows that stress during critical early periods can increase the risk of adult depression substantially, with effects that depend on timing, severity, and context. Early-life stress is also linked to persistent changes in how the brain responds to later stress, especially within the nucleus accumbens.
The Mount Sinai team focused on epigenetic regulation — chemical modifications that change gene activity without altering DNA sequence. Using unbiased, open-ended methods, they searched broadly among hundreds of possible histone and chromatin changes to find which specific epigenetic marks are most affected by early-life stress in the nucleus accumbens.
Proteomics analyses identified H3K79me2 (dimethylation of lysine 79 on histone H3) as the epigenetic mark most strongly regulated by early-life stress in this brain region. Complementary RNA sequencing showed that DOT1L, the enzyme that catalyzes H3K79 methylation, was the most highly regulated epigenetic enzyme. Together, these unbiased approaches converged on the DOT1L–H3K79me2 pathway as a critical mediator of lasting stress effects.
Importantly, the change in H3K79me2 was cell-type specific: early-life stress selectively altered this mark in D2-type medium spiny neurons within the nucleus accumbens. These neurons are central to reward and motivation circuits, and the epigenetic reprogramming observed here increases the cells’ vulnerability to a second stress exposure in adulthood.
Senior author Eric J. Nestler, MD, PhD, Director of The Friedman Brain Institute, emphasizes the value of the unbiased strategy: “By surveying many possible modifications, we were able to pinpoint one histone change out of hundreds that mediates how early stress enhances lifetime susceptibility to stress and possibly to depressive illness.”
Functional experiments confirmed the causal role of DOT1L and H3K79me2. Increasing DOT1L levels in D2 medium spiny neurons made animals more vulnerable to stress, while reducing DOT1L produced the opposite, protective effect. RNA sequencing further showed that DOT1L overexpression reproduces many of the gene expression changes induced by early-life stress, and DOT1L knockdown blocks those changes.
Building on these mechanistic findings, the researchers tested pinometostat, a selective small-molecule inhibitor of DOT1L that is currently being developed as a cancer therapy and is in advanced clinical trials for acute myeloid leukemia. In the first preclinical exploration of this compound for stress-related brain effects, twice-daily systemic administration reversed the increased stress susceptibility produced by early-life stress in adult animals, with no detectable adverse effects in the experimental setting.
“These results are encouraging because they demonstrate a pathway that can be targeted pharmacologically to reduce the long-term behavioral effects of early-life stress,” says Dr. Kronman. “New treatments are urgently needed: a substantial proportion of people with depression do not respond adequately to current therapies.”
The study represents a collaborative effort that included investigators from the Perelman School of Medicine at the University of Pennsylvania and the Department of Neurology at Massachusetts General Hospital.
Funding: This research was supported by grants from the National Institute of Mental Health and the Hope for Depression Research Foundation.
About this epigenetics and stress research news
Source: Mount Sinai Hospital
Contact: Elizabeth Dowling – Mount Sinai Hospital
Image: The image is in the public domain
Original Research: Closed access. “Long-term behavioral and cell-type-specific molecular effects of early life stress are mediated by H3K79me2 dynamics in medium spiny neurons” by Hope Kronman, Angélica Torres-Berrío, Simone Sidoli, Orna Issler, Arthur Godino, Aarthi Ramakrishnan, Philipp Mews, Casey K. Lardner, Eric M. Parise, Deena M. Walker, Yentl Y. van der Zee, Caleb J. Browne, Brittany F. Boyce, Rachael Neve, Benjamin A. Garcia, Li Shen, Catherine J. Peña & Eric J. Nestler. Nature Neuroscience.
Abstract
Long-term behavioral and cell-type-specific molecular effects of early life stress are mediated by H3K79me2 dynamics in medium spiny neurons
Animals that are susceptible to chronic social defeat stress show depression-related behaviors and altered transcription across limbic brain regions, with pronounced changes in the nucleus accumbens (NAc). Early-life stress (ELS) increases susceptibility to adult stress, yet long-lasting changes in transcriptional control mechanisms in the NAc remained understudied. This work examined durable histone modification changes in the NAc of male and female mice following ELS. The study found that dimethylation of lysine 79 on histone H3 (H3K79me2) and the enzymes regulating this mark (DOT1L and KDM2B) are enriched in D2-type medium spiny neurons and are essential for expression of ELS-induced stress susceptibility. Genome-wide mapping of this histone modification revealed the transcriptional networks it regulates. Finally, systemic administration of a DOT1L inhibitor reversed ELS-induced behavioral deficits, underscoring the potential clinical relevance of this epigenetic mechanism.