Although little is known about the regulation of histone modifications in human brain, alterations in histone modification levels, including H3 and H4 acetylation, were used to define subgroups for certain diseases, including adenomas and carcinomas.64- 71 In analogy to these examples from clinical pathology, we conducted subgroup analyses for each histone modification separately. We dichotomized the cohort of subjects with schizophrenia into subgroups based on modified histone levels of 1.3 or greater relative to matched controls. After the first part of the study, which was conducted on 21 matched pairs, we identified 6 subjects with schizophrenia who showed H3meR17 levels of 1.3 or greater relative to their matched controls (Schizo-H3meR17≥1.3C). This subgroup of subjects with schizophrenia (n = 6) showed a significant decrease in the expression of 3 metabolic transcripts, CRYM, CYTOC/CYC1, and MDH (t test, P = .03), and a tendency for a decrease in OAT transcripts (P < .1) compared with the remaining 15 patients with schizophrenia. Next, we sought to confirm the association between H3 methylation and down-regulated gene expression for CRYM, CYTOC/CYC1, MDH, and OAT transcripts in the PFC of subjects with schizophrenia. To this end, we studied an additional set of 40 samples consisting of 20 matched pairs of subjects with schizophrenia and controls. Immunoreactivity for H3meR17 was again measured using immunoblotting. The messenger RNA levels for each of the 4 genes were measured using real-time RT-PCR and FAM dye-labeled TaqMan MGB probes. Of these additional 20 subjects with schizophrenia, 2 showed H3meR17 levels of 1.3 or greater relative to their matched controls. Thus, 8 (20%) of 41 subjects with schizophrenia showed levels of H3meR17 of 1.3 or greater relative to their matched controls. We first compared gene expression differences between the Schiz-H3meR17≥1.3C subgroup (n = 8) and the remaining 33 subjects with schizophrenia (Figure 7A). For each of the 41 subjects with schizophrenia, levels of metabolic transcript were normalized to those of matched controls. The 8 subjects in the Schiz-H3meR17≥1.3C subgroup, but not the remaining subjects with schizophrenia (the Schiz-H3meR17<1.3C subgroup), were consistently affected by decreased metabolic gene expression (Figure 7A). Each case was scored from –4 to 0, with –4 defining cases that showed a decrease in 4 of 4 transcripts relative to matched controls. The Schiz-H3meR17≥1.3C subgroup (n = 8) scored significantly lower compared with the Schiz-H3meR17<1.3C subgroup (n = 33) (mean ± SEM, –3.63 ± 0.26 vs –1.7 ± 0.25; Mann-Whitney z = –3.24; P < .005, 2-tailed). We conclude that expression of a set of 4 metabolic genes (CRYM, CYTOC/CYC1, MDH, and OAT) is significantly decreased in the Schiz-H3meR17≥1.3C subgroup. The 4 transcripts (CRYM, MDH, CYTOC/CYC1, and OAT) were strongly correlated (r = 0.55-0.83; P < .005-.0001), which indicates that they are not independently regulated. To examine whether the 4 metabolic transcripts are significantly decreased in the Schiz-H3meR17≥1.3C subgroup, we calculated, for each subject and matched control, the mean difference in expression levels for CRYM, MDH, CYTOC/CYC1, and OAT. The Schiz-H3meR17≥1.3C subgroup (n = 8) showed a significant deficit in expression of the 4 transcripts compared with matched controls (Δ log mean[Schiz-H3meR17≥1.3C – Control] ± SEM, –0.25 ± 0.09; t = 2.61; P = .04, 2-tailed t test) (Figure 7B). In contrast, the remaining 33 schizophrenic subjects showed no significant deficits in expression of the 4 transcripts compared with matched controls (Δ log mean[Schiz-H3meR17<1.3C – Control] ± SEM, 0.02 ± 0.06; t = 0.36; P = .7) (Figure 7B). We conclude that the set of 4 metabolic transcripts is significantly decreased in the Schiz-H3meR17≥1.3C subgroup of subjects with schizophrenia compared with other subjects with schizophrenia and matched controls.