# Epigenetic Signatures of Social Defeat Stress Varying Duration

## TL;DR

This study explores how different durations of social defeat stress affect the prefrontal cortex epigenetics and behavior in mice, linking changes to depression-related genes.

## Contribution

The study reveals that prolonged social defeat stress alters H3K4me3 epigenetic marks and identifies gene clusters linked to depression and synaptic function.

## Key findings

- A 30-day stress period causes more severe depressive-like behavior in mice compared to shorter durations.
- Stress alters H3K4me3 density at nucleosomal peaks, with promoter regions showing differential enrichment.
- Genes like Mef2c, Nr4a3, Shank2, Shank1, and Gria2 are linked to stress sensitivity and depression.

## Abstract

Stress-induced mental disorders, including depression and anxiety disorders, constitute a global issue in contemporary society due to treatment complexity and the diversity of manifestations. Understanding the molecular mechanisms of these disorders presents a significant challenge for neurobiology. We investigated the effects of social defeat stress (SDS) of varying durations (10 and 30 days) on behavioral patterns and the H3K4me3 (trimethylation at the 4th lysine residue of histone H3) landscape in the prefrontal cortex of C57BL/6 mice. Furthermore, we compared these data with previously published H3K4me3 landscape data obtained after 15 days of SDS and transcriptomic data collected after 10, 15, and 30 days. We discovered that a 30-day period of stress results in more pronounced depressive-like behavior. SDS induces slight alterations in the H3K4me3 density across numerous nucleosomal peaks. The analysis of differential enrichment peaks of H3K4me3 in promoter regions following varying durations of SDS revealed that the aggregation of multiple H3K4me3 nucleosome peaks in the promoter region functions as a QR code, likely affecting the promoter’s state regarding the accessibility of transcription factors. Furthermore, we identified a cluster of genes in the promoter regions exhibiting differential enrichment peaks of H3K4me3 following SDS of any duration. This cluster includes genes encoding transcription factors such as Mef2c and Nr4a3, as well as postsynaptic density proteins (Shank2, Shank1, and Gria2), which are associated with stress sensitivity and the onset of depression; their protein products are involved in synaptic transmission and signal transduction mechanisms. The comparison of ChIP-seq and RNA-seq data following varying durations of SDS enabled a deeper insight in to the dynamics of SDS-induced changes. Together, these findings provide a better understanding of the molecular mechanisms of SDS in the prefrontal cortex.