ABSTRACT
Objective: Cocaine use disorders (CUDs) represent a major public health problem in many countries. To better understand the interaction between the environmental modulations and phenotype, the aim of the present study was to investigate the DNA methylation pattern of CUD patients, who had concomitant cocaine and crack dependence, and healthy controls. Methods: We studied DNA methylation profiles in the peripheral blood of 23 CUD patients and 24 healthy control subjects using the Illumina Infinium HumanMethylation450 BeadChip arrays. Results: Comparison between CUD patients and controls revealed 186 differentially methylated positions (DMPs; adjusted p-value [adjP] < 10-5) related to 152 genes, with a subset of CpGs confirmed by pyrosequencing. DNA methylation patterns discriminated CUD patients and control groups. A gene network approach showed that the EHMT1, EHMT2, MAPK1, MAPK3, MAP2K1, and HDAC5 genes, which are involved in transcription and chromatin regulation cellular signaling pathways, were also associated with cocaine dependence. Conclusion: The investigation of DNA methylation patterns may contribute to a better understanding of the biological mechanisms involved in CUD.
Subject(s)
Humans , Male , Adult , Young Adult , Crack Cocaine , DNA Methylation , Cocaine-Related Disorders/genetics , Cocaine-Related Disorders/blood , Genome-Wide Association Study/methods , Case-Control Studies , Linear Models , Histone-Lysine N-Methyltransferase/genetics , Statistics, Nonparametric , Mitogen-Activated Protein Kinase 1/genetics , MAP Kinase Kinase 1/genetics , Mitogen-Activated Protein Kinase 3/genetics , Gene Regulatory Networks , High-Throughput Nucleotide Sequencing , Histocompatibility Antigens/genetics , Histone Deacetylases/geneticsABSTRACT
No abstract available.
Subject(s)
Adult , Aged , Female , Humans , Male , Middle Aged , Pregnancy , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Cyclophosphamide/therapeutic use , Doxorubicin/therapeutic use , Immunoglobulin Variable Region/genetics , Leukemia, Hairy Cell/drug therapy , Lymphoma, Non-Hodgkin/drug therapy , MAP Kinase Kinase 1/genetics , Mutation , Polymorphism, Single Nucleotide , Prednisone/therapeutic use , Proto-Oncogene Proteins B-raf/genetics , Real-Time Polymerase Chain Reaction , Vincristine/therapeutic useABSTRACT
It has been shown that neural cell adhesion molecule (NCAM)-induced neuronal differentiation is extracellular signal-regulated kinase (ERK)-dependent. However, an involvement of the mitogen activated protein kinase (MAPK) kinase (MEK), an upstream kinase of ERK, has not been directly demonstrated in this process. Therefore, we investigated whether the MEK1 plays a critical role in the NCAM-induced neuronal differentiation of hippocampal neural progenitor cells (NPCs). NPCs were transiently transfected with expression plasmids encoding activated or dominant negative (DN) forms of MEK1. The expression of DN MEK1 inhibited neuronal phenotype acquisition and soluble NCAM rescued the defect in the neuronal phenotype acquisition in DN-MEK1-transfected cells, suggesting that NCAM might contribute to the neuronal differentiation via distinct, parallel pathways including the MEK pathway. In cells expressing wild type MEK1 or constitutively active MEK1 on the other hand, the percentage of cells positive for beta-tubulin type III (Tuj1), a marker for early postmitotic neurons, was higher than seen in vector-transfected cells. These results suggest that the activation of MEK1 is required for obtaining neuronal phenotype in NPCs.