Dimethylated lysine 9 of histone 3 is elevated in schizophrenia and exhibits a divergent response to histone deacetylase inhibitors in lymphocyte cultures.

BACKGROUND: A restrictive chromatin state has been thought to be operant in the pathophysiology of schizophrenia. Our objective was to ascertain whether differences exist between baseline levels of a repressive chromatin mark such as dimethylated lysine 9 of histone 3 (H3K9me2) in patients with schizophrenia and healthy controls and whether a histone deacetylase (HDAC) inhibitor in an in vitro assay would differentially affect chromatin structure based on diagnosis.
METHODS: We obtained blood samples from 19 healthy controls and 25 patients with schizophrenia and isolated their lymphocytes. We measured baseline H3K9me2 levels (normalized to total histone 1) in the lymphocytes from all participants via Western blot analysis. To examine the effects of an HDAC inhibitor on H3K9me2, we cultured the lymphocytes from participants with trichostatin A (TSA) for 24 hours and then measured changes in H3K9me2 relative to the control condition (dimethyl sulfoxide).
RESULTS: Patients with schizophrenia had significantly higher mean baseline levels of H3K9me2 than healthy controls (6.52 v. 2.78, p = 0.028). Moreover, there was a significant negative correlation between age at onset of illness and levels of H3K9me2 (Spearman's rho = -0.588, p = 0.008). In the lymphocyte cultures, TSA induced divergent responses in terms of H3K9me2 levels from patients with schizophrenia compared with healthy controls (F(1,14) = 5.082, p = 0.041). LIMITATIONS: The use of lymphocytes to study schizophrenia has its limitations because they may not be appropriate models of synaptic activity or other brain-specific activities.
CONCLUSION: Our results provide further evidence that schizophrenia is associated with a restrictive chromatin state that is also less modifiable using HDAC inhibitors.