Histone modifications, DNA methylation, and Schizophrenia

Studies have demonstrated that several schizophrenia candidate genes are especially susceptible to changes in transcriptional activity as a result of histone modifications and DNA methylation. Increased expression of epigenetic enzymes which generally reduce transcription have been reported in schizophrenia postmortem brain samples. An abnormal chromatin state leading to reduced candidate gene expression can be explained by aberrant coordination of epigenetic mechanisms in schizophrenia. Dynamic epigenetic processes are difficult to study using static measures such as postmortem brain samples. Therefore, we have developed a model using cultured peripheral blood mononuclear cells (PBMCs) capable of pharmacologically probing these processes in human subjects. This approach has revealed several promising findings indicating that schizophrenia subject PBMC chromatin may be less capable of responding to agents which normally ‘open’ chromatin. We suggest that the ability to appropriately modify chromatin structure may be a factor in treatment response. Several pharmacological approaches for targeting epigenetic processes are reviewed.