Introduction: Bipolar disorder (BD) is severe mental illnesses defined by poor health outcomes, global disability, and public health burden. 2% of the population is affected by BD worldwide. Briefly, BD is characterized by acute episodes including depressive, and/or manic features. The etiology of bipolar disorder, remains poorly understood. However, multiple environmental factors have been demonstrated to influence the pathogenesis of BD. Recent preclinical and in-vitro studies find that altered epigenetic mechanisms such as DNA methylation are associated with altered the levels of gene expression in BD. In fact, alterations of DNA methylation of genes are important for the neuropathological aspects of BD such as dopaminergic, serotoninergic, and Brain-Derived Neurotrophic Factor (BDNF) pathways.
DNA methylation is the main mechanism of epigenetics. DNA methyl transferases (DNMTs) catalyze methylation of DNA. DNMT1 encodes the maintenance methyltransferase and DNMT3A/DNMT3B encode the de novo methyltransferases. In contrast TETs (family of proteins) initiate de methylation (by converting 5mc to 5hmc). 5hmc plays significant role in the epigenetic regulation of neuronal functions.
MB-COMT is a risk factor for BD. Zhang et al. have determined the level methylation of COMT and PPIEL genes in BD patients. Scientists have some tests on twins that their result indicated that the methylation levels of five CpG sites in PPIEL were reduced in affected twins as well as BD TYPE II patients compared with controls and they investigated the level of PPIEL expression. PPIEL in BD pathophysiology could be used as diagnostic testing in BD patients. Another candidate gene involved in the pathophysiology of BD is BDNF. BDNF dysregulation results in the disruption of GABAergic neurons suggesting that BDNF stimulates GAD67 expression, and the expression of both genes is reduced in psychiatric disorders. In BD type II patients have been found the enhanced levels of DNA methylation at the promoter of PDYN (prodynorohin, one of downstream genes of BDNF in the pathway of ethanol intake) gene in PBMCs. Receptors of PDYN is KOP. The epigenetic regulation of PDYN can be used to design a new diagnostic biomarker as well as a medication in BD patients without the possible side effects of KOP agonists. PBMCs cells are appropriate for the study of DNA methylation. Abdolmaleky found hypomethylation of DTNBP1 promoter in BD patients. DTNBP1 binds to GAD1, BDNF and RELN. The expression of RELN is regulated by DNA Methylation and reduced levels of RELN expression in patients BD have been associated with an up-regulation of DNMT1 and DNMT3a expression. Ludwing and Dwivedi have stated that the methylation levels of RELN promoter increased in BD and schizophrenia patients.
Overall DNA methylation seems to play a critical role in BD pathophysiology. Therefore these markers are likely to be clinically useful in the near future to design diagnostic and therapeutic biomarkers. However, further studies are needed in order to evaluate the roles of DNA methylation in the etiology and neurobiology of BD.
Methods: Bipolar disorder (BD) is severe mental illnesses defined by poor health outcomes, global disability, and public health burden. 2% of the population is affected by BD worldwide. Briefly, BD is characterized by acute episodes including depressive, and/or manic features. The etiology of bipolar disorder, remains poorly understood. However, multiple environmental factors have been demonstrated to influence the pathogenesis of BD. Recent preclinical and in-vitro studies find that altered epigenetic mechanisms such as DNA methylation are associated with altered the levels of gene expression in BD. In fact, alterations of DNA methylation of genes are important for the neuropathological aspects of BD such as dopaminergic, serotoninergic, and Brain-Derived Neurotrophic Factor (BDNF) pathways.
DNA methylation is the main mechanism of epigenetics. DNA methyl transferases (DNMTs) catalyze methylation of DNA. DNMT1 encodes the maintenance methyltransferase and DNMT3A/DNMT3B encode the de novo methyltransferases. In contrast TETs (family of proteins) initiate de methylation (by converting 5mc to 5hmc). 5hmc plays significant role in the epigenetic regulation of neuronal functions.
MB-COMT is a risk factor for BD. Zhang et al. have determined the level methylation of COMT and PPIEL genes in BD patients. Scientists have some tests on twins that their result indicated that the methylation levels of five CpG sites in PPIEL were reduced in affected twins as well as BD TYPE II patients compared with controls and they investigated the level of PPIEL expression. PPIEL in BD pathophysiology could be used as diagnostic testing in BD patients. Another candidate gene involved in the pathophysiology of BD is BDNF. BDNF dysregulation results in the disruption of GABAergic neurons suggesting that BDNF stimulates GAD67 expression, and the expression of both genes is reduced in psychiatric disorders. In BD type II patients have been found the enhanced levels of DNA methylation at the promoter of PDYN (prodynorohin, one of downstream genes of BDNF in the pathway of ethanol intake) gene in PBMCs. Receptors of PDYN is KOP. The epigenetic regulation of PDYN can be used to design a new diagnostic biomarker as well as a medication in BD patients without the possible side effects of KOP agonists. PBMCs cells are appropriate for the study of DNA methylation. Abdolmaleky found hypomethylation of DTNBP1 promoter in BD patients. DTNBP1 binds to GAD1, BDNF and RELN. The expression of RELN is regulated by DNA Methylation and reduced levels of RELN expression in patients BD have been associated with an up-regulation of DNMT1 and DNMT3a expression. Ludwing and Dwivedi have stated that the methylation levels of RELN promoter increased in BD and schizophrenia patients.
Overall DNA methylation seems to play a critical role in BD pathophysiology. Therefore these markers are likely to be clinically useful in the near future to design diagnostic and therapeutic biomarkers. However, further studies are needed in order to evaluate the roles of DNA methylation in the etiology and neurobiology of BD.
Results: Bipolar disorder (BD) is severe mental illnesses defined by poor health outcomes, global disability, and public health burden. 2% of the population is affected by BD worldwide. Briefly, BD is characterized by acute episodes including depressive, and/or manic features. The etiology of bipolar disorder, remains poorly understood. However, multiple environmental factors have been demonstrated to influence the pathogenesis of BD. Recent preclinical and in-vitro studies find that altered epigenetic mechanisms such as DNA methylation are associated with altered the levels of gene expression in BD. In fact, alterations of DNA methylation of genes are important for the neuropathological aspects of BD such as dopaminergic, serotoninergic, and Brain-Derived Neurotrophic Factor (BDNF) pathways.
DNA methylation is the main mechanism of epigenetics. DNA methyl transferases (DNMTs) catalyze methylation of DNA. DNMT1 encodes the maintenance methyltransferase and DNMT3A/DNMT3B encode the de novo methyltransferases. In contrast TETs (family of proteins) initiate de methylation (by converting 5mc to 5hmc). 5hmc plays significant role in the epigenetic regulation of neuronal functions.
MB-COMT is a risk factor for BD. Zhang et al. have determined the level methylation of COMT and PPIEL genes in BD patients. Scientists have some tests on twins that their result indicated that the methylation levels of five CpG sites in PPIEL were reduced in affected twins as well as BD TYPE II patients compared with controls and they investigated the level of PPIEL expression. PPIEL in BD pathophysiology could be used as diagnostic testing in BD patients. Another candidate gene involved in the pathophysiology of BD is BDNF. BDNF dysregulation results in the disruption of GABAergic neurons suggesting that BDNF stimulates GAD67 expression, and the expression of both genes is reduced in psychiatric disorders. In BD type II patients have been found the enhanced levels of DNA methylation at the promoter of PDYN (prodynorohin, one of downstream genes of BDNF in the pathway of ethanol intake) gene in PBMCs. Receptors of PDYN is KOP. The epigenetic regulation of PDYN can be used to design a new diagnostic biomarker as well as a medication in BD patients without the possible side effects of KOP agonists. PBMCs cells are appropriate for the study of DNA methylation. Abdolmaleky found hypomethylation of DTNBP1 promoter in BD patients. DTNBP1 binds to GAD1, BDNF and RELN. The expression of RELN is regulated by DNA Methylation and reduced levels of RELN expression in patients BD have been associated with an up-regulation of DNMT1 and DNMT3a expression. Ludwing and Dwivedi have stated that the methylation levels of RELN promoter increased in BD and schizophrenia patients.
Overall DNA methylation seems to play a critical role in BD pathophysiology. Therefore these markers are likely to be clinically useful in the near future to design diagnostic and therapeutic biomarkers. However, further studies are needed in order to evaluate the roles of DNA methylation in the etiology and neurobiology of BD.
Conclusion: Bipolar disorder (BD) is severe mental illnesses defined by poor health outcomes, global disability, and public health burden. 2% of the population is affected by BD worldwide. Briefly, BD is characterized by acute episodes including depressive, and/or manic features. The etiology of bipolar disorder, remains poorly understood. However, multiple environmental factors have been demonstrated to influence the pathogenesis of BD. Recent preclinical and in-vitro studies find that altered epigenetic mechanisms such as DNA methylation are associated with altered the levels of gene expression in BD. In fact, alterations of DNA methylation of genes are important for the neuropathological aspects of BD such as dopaminergic, serotoninergic, and Brain-Derived Neurotrophic Factor (BDNF) pathways.
DNA methylation is the main mechanism of epigenetics. DNA methyl transferases (DNMTs) catalyze methylation of DNA. DNMT1 encodes the maintenance methyltransferase and DNMT3A/DNMT3B encode the de novo methyltransferases. In contrast TETs (family of proteins) initiate de methylation (by converting 5mc to 5hmc). 5hmc plays significant role in the epigenetic regulation of neuronal functions.
MB-COMT is a risk factor for BD. Zhang et al. have determined the level methylation of COMT and PPIEL genes in BD patients. Scientists have some tests on twins that their result indicated that the methylation levels of five CpG sites in PPIEL were reduced in affected twins as well as BD TYPE II patients compared with controls and they investigated the level of PPIEL expression. PPIEL in BD pathophysiology could be used as diagnostic testing in BD patients. Another candidate gene involved in the pathophysiology of BD is BDNF. BDNF dysregulation results in the disruption of GABAergic neurons suggesting that BDNF stimulates GAD67 expression, and the expression of both genes is reduced in psychiatric disorders. In BD type II patients have been found the enhanced levels of DNA methylation at the promoter of PDYN (prodynorohin, one of downstream genes of BDNF in the pathway of ethanol intake) gene in PBMCs. Receptors of PDYN is KOP. The epigenetic regulation of PDYN can be used to design a new diagnostic biomarker as well as a medication in BD patients without the possible side effects of KOP agonists. PBMCs cells are appropriate for the study of DNA methylation. Abdolmaleky found hypomethylation of DTNBP1 promoter in BD patients. DTNBP1 binds to GAD1, BDNF and RELN. The expression of RELN is regulated by DNA Methylation and reduced levels of RELN expression in patients BD have been associated with an up-regulation of DNMT1 and DNMT3a expression. Ludwing and Dwivedi have stated that the methylation levels of RELN promoter increased in BD and schizophrenia patients.
Overall DNA methylation seems to play a critical role in BD pathophysiology. Therefore these markers are likely to be clinically useful in the near future to design diagnostic and therapeutic biomarkers. However, further studies are needed in order to evaluate the roles of DNA methylation in the etiology and neurobiology of BD.
Keywords: bipolar disorder, DNA methylation, diagnostic biomarker, therapeutic targets