Fig. 4: RNA bulk sequencing reveals transcription factor 4 as a potential regulator of early life stress-induced effects on the brain that interact with FKBP51 in glutamatergic forebrain neurons.

Bulk mRNA sequencing was performed on the hippocampus of female mice of the first cohort. A A clear differential expression profile was found for the effects of genotype. Furthermore, a weighted gene co-expression analysis (WGCNA) revealed 18 co-expressed gene modules that were associated with effects of genotype, ELS exposure or their interaction (B). One of these modules was associated not only with ELS exposure but was also associated with the interaction of ELS and Fkbp5 genotype. C Subsequently, a transcription factor enrichment analysis was performed for the dark orange module, which resulted in 10 enriched transcription factors. Using the software Knowing01, all genes that are regulated by the enriched transcription factors were overlaid with datasets from human psychiatric GWAS studies and the hub genes of the dark orange module (D). The right panel (D) shows which genes are regulated by specific enriched transcription factors and their resulting (indirect) overlap with the datasets. This revealed that the transcription factor 4 (TCF4) regulates the largest number of genes that had an overlap with any of the datasets. Moreover, it is the only enriched transcription factor that regulates a gene that was associated with early life adversity in females (Slc17a6; yellow dot).