The molecular pathology of schizophrenia—Focus on histone and DNA modifications

Dysfunction of cerebral cortex and other brain regions in schizophrenia is often accompanied by dysregulated expression of numerous genes. However, the underlying genetic risk architecture remains unclear for a large majority of cases. Therefore, the study of epigenetic regulators of gene expression, including covalent modifications of DNA and nucleosome core histones, offers an attractive alternative to further explore the molecular pathology of schizophrenia beyond the level of RNA quantification. Several studies reported alterations in DNA cytosine methylation and histone methylation at specific genes and promoters in postmortem brain of subjects with schizophrenia, often in conjunction with changes in levels of the corresponding RNAs. While evidence for such “epigenetic dysregulation” is increasing, many of the reported alterations await independent replication. Interestingly, studies across the lifespan indicate that DNA and histone methylation markings are developmentally regulated in human cerebral cortex, suggesting that at least some of the epigenetic changes in the brain of adult subjects with schizophrenia reflect disordered neurodevelopment.