Pathogenic histone modifications in schizophrenia are targets for therapy

Almost four decades ago an altered chromatin structure was described in the neutrophils of patients with SCZ. More recent studies reported an increase in the level of histone 3-(methyl) arginine 17 associated with decreased expression of several metabolic genes in the prefrontal cortex of SCZ patients. Transcriptome analyses also revealed aberrant expression of histone deacetylase3 (HDAC3) in the temporal cortex, and dysregulation of many histone- related genes in the blood of SCZ patients. While there are reports on increased expression of HDAC1 in the frontal cortex and hippocampus of SCZ patients and an inverse correlation between the expression of GAD67 (GAD1) and the expression of HDAC1, HDAC3 and HDAC4, in studies using transgenic mice expressing HDAC1 in the prefrontal cortex uncovered deficit in working memory and down-regulation of several genes linked to SCZ. Consistent with these observations, valproate was shown to increase H3 acetylation in lymphocytes of SCZ patients as well as H3K9, K14 acetylation of the GAD67 promoter region. Additionally, clozapine and sulpiride were shown to facilitate valproate-induced chromatin remodeling. Furthermore, in large-scale GWAS studies genes involved in histone methylation processing exhibited the strongest association with major psychiatric diseases, including SCZ. In other studies, an increased baseline level of H3K9me2 (a repressive chromatin mark) was also observed in lymphocytes and in postmortem brain tissues of SCZ patients, coupled with a younger age of disease onset. While in general, there is an age-dependent increase in H3K4me at the GAD1 promoter, a decrease of GAD1 promoter H3K4me associated with reduced GAD1 expression has been reported in the prefrontal cortex of SCZ patients that was due to MLL1 histone methyltransferase dysfunction in neurons. Interestingly, higher order chromatin structures that delineate chromosomal looping and modulate physical contact of promoter regions to cis acting enhancers/silencers are also altered at the GAD1 promoter region associated with GAD1 expression changes in the frontal cortex of SCZ patients. More recent studies also report aberrant ubiquitination, ufmylation, SUMOylation, and NEDD8ylation in the superior temporal gyrus of SCZ patients.