Epigenetic effects of drugs on early human neural development

Abstract

The phenotype and function of cells are dependent on the sets of genes that are active or silenced in a given cell type. One important determinant of gene activity is signaling processes that lead to the activation of transcription factors. However, gene activity is also determined by the local chromatin structure. Epigenetic modifications, such as the methylation of DNA bases, or the posttranslational modification of histone proteins strongly affect the chromatin. Such chromatin changes have been little considered yet as target of neurotoxicants. We examined here, how the developmental neurotoxicant valproic acid, and other histone deacetylase inhibitors affected epigenetic modifications at the promoters of key developmental genes (e.g. Pax6). As model system, we used human pluripotent stem cells developing to neural precursor cells, i.e. a developmental stage corresponding to the early neural tube in fetuses. We identified epigenetic changes related to transient drug effects (histone acetylation), and other histone modifications (lysine methylation) that correlated well with permanent developmental disturbances. The findings of persistent methylation changes after drug exposure offer an explanation for persistent drug effects on neurodevelopment even after the initial drug exposure has ended.