Many of us dream of a quick fix to being so stressed all the time, and now that reality may not be so far off thanks to the identification of a histone modification behind the life-long effects of early-life stress (ELS).
The nucleus accumbens is a brain region important for dopamine signaling and reward behavior. ELS is a major risk factor for depression, and it increases stress susceptibility later in life, particularly in the nucleus accumbens on a molecular level. To understand what drives these changes, researchers from Eric Nestler’s group (Icahn School of Medicine at Mount Sinai) looked at histone posttranslational modification (PTMs) across different developmental time points, finding:
- Tandem mass spectrometry revealed that several histone posttranslational modifications are altered throughout development in the nucleus accumbens following ELS
- ELS induces demethylation of lysine 79 of histone H3 (H3K79me2) as male mice age
- This is accompanied by changes in gene expression of writer (Dot1l) and eraser (Kdm2b) enzymes (tested by qPCR)
- DOT1L protein levels also increase in male ELS mice with age
- Specifically, in dopamine receptor 2 (D2)-type medium spiny neurons (FACS isolated), expression of both Dot1l and Kdm2b is induced by ELS with age
To test if these enzymes mediate later stress susceptibility, these smart scientists used cell-type specific miRNA knockdown and overexpression vectors for Dot1l and Kdm2b.
- Dot1l knockdown in ELS adults reversed stress susceptibility in several behavioral tests, while overexpression in standard animals replicated the stress phenotype
- Conversely, overexpression of Kdm2b reversed ELS-induced stress susceptibility and knockdown increased it
- RNA-seq revealed transcriptional signatures of ELS that are replicated by Dot1l overexpression
- Expression profiles of specific genes correlate with behavioral outcomes related to the stress response
- These transcriptional signatures also correlate with genome-wide H3K79me2 patterns profiled by ChIP-seq
Finally, intraperitoneal injection of pinometostat, a DOT1L inhibitor, rescued stress-susceptible behavior and H3K79me2 levels in the nucleus accumbens of ELS mice. This is exciting since this drug is already in clinical trials for leukemia.
Senior author Eric Nestler explains, “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.” First author Hope Kronman shares, “We’re greatly encouraged by these findings which support the possible use of the novel early life stress mechanism we identified for therapeutic purposes. 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.”
Alleviate your stress with Nature Neuroscience, March 2021.