Transcription factor binding and individual genetic risk for valproate teratogenicity

We then profiled coexpression between EP300 and other TFs in differentiating neurons derived from human embryonic stem cells (hESCs) exposed to VPA at 300µM and 700 µM, or unexposed, and a reference map generated using public data. Almost all coexpressed pairs observed in the cell assay data were also observed in the reference map. In contrast, only 30% (119/400) of the coexpressed pairs observed in unexposed cells were present in cells exposed to VPA; suggesting that VPA activates alternative biologically valid, but context inappropriate, signaling cascades.

Our findings suggest that VPA-induced disruption of EP300-related regulation is common across birth defect types and that genetic variation can modify subsequent transcriptional dysregulation, explaining why only some pregnancies are affected. The results have implications for the development of genetic risk biomarkers and safer drugs.