RESUMEN
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.
Asunto(s)
Humanos , Masculino , Adulto , Adulto Joven , Cocaína Crack , Metilación de ADN , Trastornos Relacionados con Cocaína/genética , Trastornos Relacionados con Cocaína/sangre , Estudio de Asociación del Genoma Completo/métodos , Estudios de Casos y Controles , Modelos Lineales , N-Metiltransferasa de Histona-Lisina/genética , Estadísticas no Paramétricas , Proteína Quinasa 1 Activada por Mitógenos/genética , MAP Quinasa Quinasa 1/genética , Proteína Quinasa 3 Activada por Mitógenos/genética , Redes Reguladoras de Genes , Secuenciación de Nucleótidos de Alto Rendimiento , Antígenos de Histocompatibilidad/genética , Histona Desacetilasas/genéticaRESUMEN
No abstract available.
Asunto(s)
Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Embarazo , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Ciclofosfamida/uso terapéutico , Doxorrubicina/uso terapéutico , Región Variable de Inmunoglobulina/genética , Leucemia de Células Pilosas/tratamiento farmacológico , Linfoma no Hodgkin/tratamiento farmacológico , MAP Quinasa Quinasa 1/genética , Mutación , Polimorfismo de Nucleótido Simple , Prednisona/uso terapéutico , Proteínas Proto-Oncogénicas B-raf/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Vincristina/uso terapéuticoRESUMEN
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.