Comparative RNA-Seq in mouse prelimbic cortex (PL)

Major depressive disorder (MDD) is a prevalent and life-threatening illness in modern society. The susceptibility to MDD is profoundly influenced by environmental factors, such as stressful lifestyle or traumatic events, which could impose maladaptive transcriptional program through epigenetic regulation. However, the underlying molecular mechanisms remain elusive. Here we report that stress-susceptible rodents exhibit lower levels of histone crotonylation in the medial prefrontal cortex (mPFC), concurrent with regional upregulation of chromodomain Y-like (CDYL), a crotonyl-CoA hydratase and histone methyllysine reader. Overexpression of CDYL in the prelimbic cortex (PL), a sub-region of mPFC, increases microdefeat-induced social avoidance behaviors and anhedonia in mice. Conversely, knockdown of CDYL in PL prevents chronic social defeat stress-induced depression-like behaviors. Mechanistically, we show that CDYL inhibits structural synaptic plasticity mainly by transcriptional repression of neuropeptide VGF, and this activity is dependent on its dual effect on regional histone crotonylation and H3K27 tri-methylation on the VGF promoter. Together, our data indicate CDYL plays a critical role in regulating stress-induced depression-like behaviors, providing a potential therapeutic target for MDD. PL tissues mRNA profiles of 8-week old Control and Susceptible mice, and AAV-GFP or AAV-CDYL virus expressed mice were generated by deep sequencing, using Illumina HiSeq 2500.