DNA-methylation gene network dysregulation in peripheral blood lymphocytes of schizophrenia patients

Abstract

The epigenetic dysregulation of the brain genome associated with the clinical manifestations of schizophrenia (SZ) includes altered DNA promoter methylation of several candidate genes. We and others have reported that two enzymes that belong to the DNA-methylation/demethylation network pathways-DNMT1 (DNA-methyltransferase) and ten-eleven translocator-1(TET1) methylcytosine deoxygenase are abnormally increased in corticolimbic structures of SZ postmortem brain. The objective of this study was to investigate whether the expression of these components of the DNA-methylation-demethylation pathways known to be altered in the brain of SZ patients are also altered in peripheral blood lymphocytes (PBL). The data show that increases in DNMT1 and TET1 and in glucocorticoid receptor (GCortR) and brain derived neurotrophic factor (BDNF) mRNAs in PBL of SZ patients are comparable to those reported in the brain of SZ patients. The finding that the expressions of DNMT1 and TET1 are increased and SZ candidate genes such as BDNF and GCortR are altered in the same direction in both the brain and PBL together with recent studies showing highly correlated patterns of DNA methylation across the brain and blood, support the hypothesis that a common epigenetic dysregulation may be operative in the brain and peripheral tissues of SZ patients.

Keywords: Brain derived neurotrophic factor (BDNF); DNA demethylation; DNA methyltransferase (DNMT); Epigenetic; Glucocorticoid receptor (GCortR); Ten-eleven-translocation hydroxylase (TET).

Figure 1

Pearson’s correlation analyses between: A) TET1 mRNA in lymphocytes and Serum ACTH levels of SZ patients (n=17); B) TET1 mRNA in lymphocytes and Serum trygliceride levels of SZ patients (n=15); C) BDNF-IXabcd mRNA and DNMT1 mRNA in lymphocytes of SZ patients (n=17). mRNA is expressed as 2^ΔCt × 10⁻⁴ vs β-actin