Background Alterations of the endocannabinoid system (ECS), composed of endogenous lipids, their target receptors and metabolic enzymes, have been associated with psychiatric disorders; yet, molecular mechanisms underlying induced adaptive transformations in the ECS are not clearly understood. Emerging insights fuel interest for the field of ‘neuroepigenetics' and, among the many genes and signalling pathways regulated by epigenetic mechanisms, ECS elements are getting more and more attention. We here studied the epigenetic and genetic regulation of ECS components, mainly focusing on type-1 cannabinoid receptor (CB1), in different psychiatric disorders such as major depressive disorder, bipolar disorder, schizophrenia, as well as eating disorders. Methods Genomic DNA and total RNA have been isolated from peripheral blood mononuclear cells (PBMCs) of patients under stable pharmacological treatment, and of healthy controls. To assess gene abundances and to quantify gene promoters DNA methylation, we used Real-Time RT-PCR and Pyrosequencing respectively. TaqMan SNP Genotyping Assays (Life Technologies) were used for genotyping 3 SNPs (rs1049353, rs806368 and rs6454674) at CB1 gene (CNR1) promoter. Results We have observed selective changes in CB1-encoding CNR1 gene expression, namely a down-regulation in individuals with major depressive disorder and an up-regulation in schizophrenic patients, who were also found to show a consistent reduction in DNA methylation at gene promoter. Moreover, rs1049353 was found to be associated to schizophrenia. No significant alterations have been observed in gene transcription regulation of any other ECS components, nor in the association of the SNPs to the different disorders. Discussion We here revealed selective changes in gene transcription regulation of ECS components, involving CNR1 gene only. Our findings suggest a complex relationship between genetic and epigenetic markers, which may enhance or mask a possible predisposition to the risk of schizophrenia. Further research is needed to investigate the nature of this interaction, and the relevance of individual differences in susceptibility to develop a psychiatric disorder. These new data hold promise also for the selection of treatment strategies for different patients.
Transcriptional regulation of endocannabinoid system genes in psychiatric disorders.
M. V. MICIONI DI BONAVENTURA;C. CIFANI;
2015-01-01
Abstract
Background Alterations of the endocannabinoid system (ECS), composed of endogenous lipids, their target receptors and metabolic enzymes, have been associated with psychiatric disorders; yet, molecular mechanisms underlying induced adaptive transformations in the ECS are not clearly understood. Emerging insights fuel interest for the field of ‘neuroepigenetics' and, among the many genes and signalling pathways regulated by epigenetic mechanisms, ECS elements are getting more and more attention. We here studied the epigenetic and genetic regulation of ECS components, mainly focusing on type-1 cannabinoid receptor (CB1), in different psychiatric disorders such as major depressive disorder, bipolar disorder, schizophrenia, as well as eating disorders. Methods Genomic DNA and total RNA have been isolated from peripheral blood mononuclear cells (PBMCs) of patients under stable pharmacological treatment, and of healthy controls. To assess gene abundances and to quantify gene promoters DNA methylation, we used Real-Time RT-PCR and Pyrosequencing respectively. TaqMan SNP Genotyping Assays (Life Technologies) were used for genotyping 3 SNPs (rs1049353, rs806368 and rs6454674) at CB1 gene (CNR1) promoter. Results We have observed selective changes in CB1-encoding CNR1 gene expression, namely a down-regulation in individuals with major depressive disorder and an up-regulation in schizophrenic patients, who were also found to show a consistent reduction in DNA methylation at gene promoter. Moreover, rs1049353 was found to be associated to schizophrenia. No significant alterations have been observed in gene transcription regulation of any other ECS components, nor in the association of the SNPs to the different disorders. Discussion We here revealed selective changes in gene transcription regulation of ECS components, involving CNR1 gene only. Our findings suggest a complex relationship between genetic and epigenetic markers, which may enhance or mask a possible predisposition to the risk of schizophrenia. Further research is needed to investigate the nature of this interaction, and the relevance of individual differences in susceptibility to develop a psychiatric disorder. These new data hold promise also for the selection of treatment strategies for different patients.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
