Distinct Expression Pattern of Epigenetic Machinery Genes in Blood Leucocytes and Brain Cortex of Depressive Patients

Abstract

In major depressive disorder (MDD), altered gene expression in brain cortex and blood leucocytes may be due to aberrant expression of epigenetic machinery coding genes. Here, we explore the expression of these genes both at the central and peripheral levels. Using real-time quantitative PCR technique, we first measured expression levels of genes encoding DNA and histone modifying enzymes in the dorsolateral prefrontal cortex (DLPFC) and cingulate cortex (CC) of MDD patients ( n = 24) and healthy controls ( n = 12). For each brain structure, transcripts levels were compared between subject groups. In an exploratory analysis, we then compared the candidate gene expressions between a subgroup of MDD patients with psychotic characteristics ( n = 13) and the group of healthy subjects ( n = 12). Finally, we compared transcript levels of the candidate genes in blood leucocytes between separate samples of MDD patients ( n = 17) and healthy controls ( n = 16). In brain and blood leucocytes of MDD patients, we identified an overexpression of genes encoding enzymes which transfer repressive transcriptional marks: HDAC4-5-6-8 and DNMT3B in the DLPFC, HDAC2 in the CC and blood leucocytes. In the DLPFC of patients with psychotic characteristics, two genes (KAT2A and UBE2A) were additionally overexpressed suggesting a shift to a more transcriptionally permissive conformation of chromatin. Aberrant activation of epigenetic repressive systems may be involved in MDD pathogenesis both in brain tissue and blood leucocytes. Electronic supplementary material The online version of this article (10.1007/s12035-018-1406-0) contains supplementary material, which is available to authorized users.

Association of Polymorphisms in Genes Involved in One-Carbon Metabolism with MTHFR Methylation Levels

“…Folate metabolism is required in all dividing cells for a proper supply of nucleotides, as well as in non-dividing cells such as neurons, for a proper repair of damaged DNA bases and for the regulation of DNA and protein methylation patterns, and therefore most of the folate-related genes are ubiquitously expressed and differentially regulated in human tissues, including blood cells [1]. Particularly, there is an indication that both DNMT3A and DNMT3B are de-methylated and expressed blood cells of healthy individuals [35,45]. Similarly, the MTHFR is expressed in blood cells [46], and the expression levels are inversely regulated by promoter methylation levels, that show a large inter-individual variability [24,35].…”

DNA Methyltransferases in Depression: An Update

“…According to a postmortem study from suicide patients with MDD, there was no significant change of DNMT3A expression in the prefrontal cortex, amygdala, and paraventricular nucleus of hypothalamus, but the DNMT3B expressions were increased in the prefrontal cortex and paraventricular nucleus and decreased in amygdala of patients compared to healthy controls (6). In another study, the DNMT3B expressions in the dorsolateral prefrontal cortex of depression patients were increased, and the DNMT3A expressions showed no change compared to those in healthy controls (7). This is consistent with a study done with peripheral white blood cells (51).…”

“…Growing evidences suggest that DNA methylation and DNMTs are involved in the development of depression (5). DNMTs expression changes have been found in different brain areas in depression patients (6,7) and animal models (8,9). Among these studies, frontal cortex and amygdala are the common affected areas in both human and animal, suggesting DNMTs may contribute to the cognitive and emotional domains of depression endophenotypes, which are also cortisol-related (10,11).…”

An epigenome-wide association study of early-onset major depression in monozygotic twins

“…Thus, a comprehensive understanding of the genetic architecture of the developing adolescent/young adult brain may be critical to identify etiological determinants of MD. Additional genes/gene regions previously linked to MD, stress, or psychiatric/substance use disorders differentiated twins with and without a lifetime history of MD (e.g., HDAC4, NRG3, CRHR2) [91][92][93][94][95][96][97] . Moreover, 6 differentially methylated and 12 variably methylated findings overlapped loci identified in a recent PGC GWAS of depression.…”