Regulation of gene transcription in bipolar disorders: Role of DNA methylation in the relationship between prodynorphin and brain derived neurotrophic factor

Abstract

Bipolar Disorder (BD) is a prevalent and disabling condition, determined by gene-environment interactions, possibly mediated by epigenetic mechanisms. The present study aimed at investigating the transcriptional regulation of BD selected target genes by DNA methylation in peripheral blood mononuclear cells of patients with a DSM-5 diagnosis of type I (BD-I) and type II (BD-II) Bipolar Disorders (n = 99), as well as of healthy controls (CT, n = 42). The analysis of gene expression revealed prodynorphin (PDYN) mRNA levels significantly reduced in subjects with BD-II but not in those with BD-I, when compared to CT. Other target genes (i.e. catechol-O-methyltransferase (COMT), glutamate decarboxylase (GAD67), serotonin transporter (SERT) mRNA levels remained unaltered. Consistently, an increase in DNA methylation at PDYN gene promoter was observed in BD-II patients vs CT. After stratifying data on the basis of pharmacotherapy, patients on mood-stabilizers (i.e., lithium and anticonvulsants) were found to have lower DNA methylation at PDYN gene promoter. A significantly positive correlation in promoter DNA methylation was observed in all subjects between PDYN and brain derived neurotrophic factor (BDNF), whose methylation status had been previously found altered in BD. Moreover, among key genes relevant for DNA methylation establishment here analysed, an up-regulation of DNA Methyl Transferases 3b (DNMT3b) and of the methyl binding protein MeCP2 (methyl CpG binding protein 2) mRNA levels was also observed again just in BD-II subjects. A clear selective role of DNA methylation involvement in BD-II is shown here, further supporting a role for BDNF and its possible interaction with PDYN. These data might be relevant in the pathophysiology of BD, both in relation to BDNF and for the improvement of available treatments and development of novel ones that modulate epigenetic signatures.

Sex differences in neural mechanisms mediating reward and addiction

“…Organizational influences: epigenetics. Although there is strong evidence for epigenetic regulation of Pdyn via DNA methylation and miRNAs within limbic brain regions [197,198], and Oprk1 via histone acetylation (acetylated histone H3 Lysine9) in the spinal cord [199], there is no direct evidence (to our knowledge) of sex differences in epigenetic regulation of either Pdyn or Oprk1.…”

Neuroplasticity, Neurotransmission and Brain-Related Genes in Major Depression and Bipolar Disorder: Focus on Treatment Outcomes in an Asiatic Sample

“…The genes we investigated regulate the functioning of systems that have been previously reported as consistently involved in the mechanisms of action of antidepressant drugs and mood stabilizers [ 15 – 19 ]. Despite this, none of the genetic variants was found significantly associated neither with antidepressant treatment in MDD, nor with mood stabilizers in BD.…”

“…These candidate genes are mainly involved in (but not limited to) monoaminergic neurotransmission, neuroplasticity and circadian rhythm pathways [ 12 – 14 ]. Mechanisms of signal transduction, transcription factors and pathways related to cellular metabolism have also been associated with mood disorder risk and response variability to pharmacological treatments [ 15 – 19 ].…”

DNA Methylation as a Biomarker of Treatment Response Variability in Serious Mental Illnesses: A Systematic Review Focused on Bipolar Disorder, Schizophrenia, and Major Depressive Disorder

“…A decrease of DNA methylation at the promoter I of BDNF was observed in the Peripheral Blood Mononuclear Cells (PBMC) of BD patients with antidepressant therapy, compared to no antidepressant therapy [ 50 ]. Similarly, patients treated with lithium or VPA displayed a decrease of DNA methylation levels, as compared to other medications [ 50 , 83 ]. A trend, yet not significant, for a decreased DNA methylation level at the BDNF promoter I was found in another study with a slightly different design [ 84 ].…”