Editors' ChoiceNeuroscience

Connect-the-DOT from early stress to depression

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Science Signaling  13 Apr 2021:
Vol. 14, Issue 678, eabi9138
DOI: 10.1126/scisignal.abi9138

Targeting the epigenetic enzyme DOT1L may reverse some behavioral effects of early-life stress.

Stress early in life is associated with a greater risk for depression and other psychiatric issues in adulthood. Persistent epigenetic changes in the brain are believed to be contributing factors. Kronman et al. found that altered expression of two epigenetic enzymes—DOT1L and KDM2B—in a specific brain region and neuron type therein mediated the link between early-life stress and later-life depression in mice. The authors used a mouse model of early-life stress in which pre-weaned pups underwent a period of daily maternal separations and were housed with inadequate bedding. Subsequently as adults, these and control mice were placed with a larger, more aggressive mouse to induce social defeat stress. Compared to the control mice, the mice that had been stressed as pups exhibited depression-like behaviors and had greater demethylation of Lys79 in histone H3 (a mark called H3K79me2) selectively in D2 dopamine receptor–positive medium spiny neurons of the nucleus accumbens (NAc). Further analysis revealed a transcriptome that was altered by H3K79 dimethylation, as well as potential integration with other histone modifications in these mice. In conjunction with increased H3K79me2 prevalence in these neurons in the NAc was increased abundance of the histone methyltransferase DOT1L and decreased abundance of the demethylase KDM2B (the writer and eraser, respectively, of this histone mark). Overexpressing DOT1L in D2-type medium spiny neurons mimicked the effects of the early-life stress model, whereas knocking it down or systemically delivering a small-molecule inhibitor of DOT1L (that is currently in phase II trials for a form of leukemia) reversed the early-life stress–induced behavioral effects. These findings reveal deeper insight into the enduring epigenetic effects of early-life stress on adult behavior and provide potential targets for therapeutically reversing them.

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