Have you ever felt stressed and even depressed? Well, a new study linking stress-induced depressive behaviors to changes in nucleosome positioning suggests that in order to relax yourself, you may first need to relax your chromatin.
Susceptibility to major depressive disorder (MDD) depends on genetic variability but also on environmental factors such as a stressful life. Chronic stress causes abnormal transcriptional regulation in limbic neural circuits such as the nucleus accumbens (NAc), which is a reward-processing region of the brain, and contributes substantially to the risk of MDD.
To get to the root of abnormal transcriptional regulation in the NAc of mouse models and depressed humans, HaoSheng Sun and colleagues at the Icahn School of Medicine at Mount Sinai, subjected validated depression mouse models to 10-min aggressive daily encounters followed by sensory contact for the rest of the day, for 10 consecutive days.
After the 10 day encounter, about 65% of the tested mice showed depression-related behavioral changes. The then used next-generation sequencing and gene expression analysis to profile the affected mice, and collaborated their findings in the NAc of post-mortem brains of depressed humans.
Here’s what they found:
- The ACF chromatin remodeling complex, which controls how tightly or loosely DNA is wrapped around histone proteins, was persistently and selectively upregulated in the NAc of mice that were susceptible to chronic social stress and in the NAc of depressed humans.
- The induction of ACF was necessary for susceptibility to stress-induced depressive-like behaviors
- Altered ACF binding in the NAc of susceptible animals after chronic stress was associated with altered nucleosome positioning, particularly at the transcriptional start site (TSS) of affected genes.
- These alterations in ACF binding and nucleosome positioning were associated with repressed expression of genes implicated in susceptibility to stress.
- Upregulation of the ISWI subunit chromatin-remodeler complex, BAZIA and ACF alone without co-occurring stress did not induce depressive-like behavior.
The team concludes that the findings “establish that the ACF complex, presumably through its effects in chromatin remodeling, is a key mediator of gene repression that contributes to stress susceptibility”.
To learn more about how nucleosomes affect your mood, head straight to Nature Medicine, September 2015.