Fig. 1.

Epigenetic impact of the pre- and postnatal environment on brain development. In the two-hit hypothesis of SZ, a predisposing genome would be considered a first hit. Environmentally induced epigenetic mechanisms acting on the genome during prenatal and postnatal development facilitate genome-wide changes in the epigenome that alter cell type-specific transcriptional profiles at distinct developmental time points. These environmental insults that then act on the predisposing genome at distinct development times represent a second hit. The subsequent mRNA alterations, in turn, produce altered protein profiles that cause deficits in multiple processes including cortical migration, chromatin remodeling, transcriptional regulation, immune-response regulation, and the formation of synaptic connections. Moreover, changes at the cellular level can translate into altered neuronal network connections that ultimately impact the phenotype of the individual. Genome-wide association and whole exome sequencing studies have identified a large number of genes associated with SZ that encode proteins that function in synapse formation, transcriptional regulation, and chromatin-remodeling pathways.