Zhubi A, Veldic M, Puri N V, Kadriu B, Caruncho H, Loza I, Sershen H, Lajtha A, Smith R C, Guidotti A, Davis J M, Costa E
Psychiatric Institute, Department of Psychiatry, College of Medicine, University of Illinois at Chicago, IL, USA.
Schizophr Res. 2009 Jun;111(1-3):115-22. doi: 10.1016/j.schres.2009.03.020. Epub 2009 Apr 21.
Several lines of schizophrenia (SZ) research suggest that a functional downregulation of the prefrontal cortex GABAergic neuronal system is mediated by a promoter hypermethylation, presumably catalyzed by an increase in DNA-methyltransferase-1 (DNMT-1) expression. This promoter hypermethylation may be mediated not only by DNMT-1 but also by an entire family of de novo DNA-methyltransferases, such as DNA-methyltransferase-3a (DNMT-3a) and -3b (DNMT-3b). To verify the existence of an overexpression of DNMT-3a and DNMT-3b in the brain of schizophrenia patients (SZP), we compared their mRNA expression in Brodmann's area 10 (BA10) and in the caudate nucleus and putamen obtained from the Harvard Brain Tissue Resource Center (Belmont, MA) from both nonpsychiatric subjects (NPS) and SZP. Our results demonstrate that DNMT-3a and DNMT-1 are expressed and co-localize in distinct GABAergic neuron populations whereas DNMT-3b mRNA is virtually undetectable. We also found that unlike DNMT-1, which is frequently overexpressed in telencephalic GABAergic neurons of SZP, DNMT-3a mRNA is overexpressed only in layer I and II GABAergic interneurons of BA10. To ascertain whether these DNMT expression differences observed in brain tissue could also be detected in peripheral tissues, we studied whether DNMT-1 and DNMT-3a mRNAs were overexpressed in peripheral blood lymphocytes (PBL) of SZP. Both DNMT-1 and DNMT-3a mRNAs are expressed in the PBL and although DNMT-3a mRNA levels in the PBL are approximately 1/10 of those of DNMT-1, the comparison of the PBL content in NPS and SZP showed a highly significant 2-fold increase of both DNMT-1 and DNMT-3a mRNA in SZP. These changes were unaffected by the dose, the duration, or the type of antipsychotic treatment. The upregulation of DNMT-1 and to a lesser extent that of DNMT-3a mRNA in PBL of SZP supports the concept that this readily available peripheral cell type can express an epigenetic variation of specific biomarkers relevant to SZ morbidity. Hence, PBL studies may become useful to investigate a diagnostic epigenetic marker of SZ morbidity.
多条精神分裂症（SZ）研究线索表明，前额叶皮质GABA能神经元系统的功能下调是由启动子高甲基化介导的，推测是由DNA甲基转移酶-1（DNMT-1）表达增加催化的。这种启动子高甲基化可能不仅由DNMT-1介导，还由整个从头DNA甲基转移酶家族介导，如DNA甲基转移酶-3a（DNMT-3a）和-3b（DNMT-3b）。为了验证精神分裂症患者（SZP）大脑中DNMT-3a和DNMT-3b是否存在过表达，我们比较了从哈佛脑组织资源中心（马萨诸塞州贝尔蒙特）获取的非精神科受试者（NPS）和SZP的布罗德曼10区（BA10）、尾状核和壳核中它们的mRNA表达。我们的结果表明，DNMT-3a和DNMT-1在不同的GABA能神经元群体中表达并共定位，而DNMT-3b mRNA几乎检测不到。我们还发现，与在SZP端脑GABA能神经元中经常过表达的DNMT-1不同，DNMT-3a mRNA仅在BA10的I层和II层GABA能中间神经元中过表达。为了确定在脑组织中观察到的这些DNMT表达差异是否也能在外周组织中检测到，我们研究了DNMT-1和DNMT-3a mRNA在SZP外周血淋巴细胞（PBL）中是否过表达。DNMT-1和DNMT-3a mRNA均在PBL中表达，尽管PBL中DNMT-3a mRNA水平约为DNMT-1的1/10，但NPS和SZP的PBL含量比较显示，SZP中DNMT-1和DNMT-3a mRNA均显著增加了2倍。这些变化不受抗精神病药物治疗的剂量、持续时间或类型的影响。SZP的PBL中DNMT-1的上调以及程度较轻的DNMT-3a mRNA的上调支持了这样一种概念，即这种易于获得的外周细胞类型可以表达与SZ发病相关的特定生物标志物的表观遗传变异。因此，PBL研究可能有助于研究SZ发病的诊断表观遗传标志物。
