Gene expression analysis in mouse brain identifies biological processes underlying stress response in Fkbp5 deficient mice

Fkbp5 encodes the FK506 binding protein 5, a glucocorticoid receptor (GR) binding protein which is an important factor in stress responses that form coping behavior. However, the results of previous studies have been controversial about the relationships between variants in Fkbp5 and stress have been controversial. To clarify the effects of the loss of Fkbp5 on the stress response, we conducted behavior test with mice following chronic restraint stress with homozygous wild type (WT) and knock-out (KO) genotypes. WT mice showed anhedonia, one of depressive-like behaviors, but KO mice did not show this symptom in sucrose preference test (SPT). To examine the molecular mechanism of this stress resilience, we performed RNAseq analysis. The results of differentially expressed gene (DEG) analysis showed that diverse biological processes related with cell-cell communication are changed by chronic stress. Weighted gene co-expression network analysis detected 60 gene modules which show varied correlation patterns with stress or Fkbp5 genotype. The expression pattern of M55 module correlated with SPT results and the gene ontology (GO) enrichment analysis in this module revealed that the genes in this module are involved in nervous system development, gland morphogenesis and inflammatory response. We identify the role of Fkbp5 KO in stress response and the transcriptome study provide insight into stress-related biological processes. mRNA profiles of prefrontal cortex (PFC) from wild type (WT) control mice, WT stressed mice and Fkbp5-/- stressed mice were produced using Illumina HiSeq 4000. Bioinformatics analyses of the transcriptome profiles indicate that a wide variety of biological processes are affected in the PFC of WT and Fkbp5-/- stressed mice. We identified the various unique gene expression patterns altered by genotype and stress. Thus, this mouse brain transcriptome data resource provides a powerful and extensive framework to identify, prioritize and test gene targets and stress response mechanisms affected by Fkbp5-/-.