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Treatment of NT2 cells with valproic acid, trichostatin A, or aza - 2 - deoxycytidine decreases Reelin promoter methylation and increases mRNA expression

Treatment of NT2 cells with valproic acid, trichostatin A, or aza - 2 - deoxycytidine decreases Reelin promoter methylation and increases mRNA expression

Society for Neuroscience Abstract Viewer & Itinerary Planner : Abstract No 313 5

An approximate 50% reduction in reelin mRNA and protein levels have been detected in post-mortem tissue of patients diagnosed with schizophrenia in all brain areas studied to date, including several cortical regions, hippocampus, and cerebellum, which is not attributable to neuronal loss. One potential mechanism of this deficit is hypermethylation of cytosines in the promoter region of the reelin gene. Cytosine hypermethylation could promote histone deacetylation, thereby inducing a closed chromatin state and repressing transcription. In support of this, the histone deacetylase inhibitor (HDAC) valproic acid (VPA) has proven beneficial as an adjunctive treatment in schizophrenia. We previously demonstrated that treatment of NT2 neuronal precursor cells with the HDAC inhibitors valproic acid, trichostatin A (TSA), or the cytosine analog aza-2'-deoxycytidine (AZA), increases reelin mRNA expression. In the current study, we show that treatment of NT2 cells with VPA (5 mM for 48 hrs), TSA (0.3 muM for 24 hrs), or AZA (5 muM for 72 hrs) significantly decreases the number of methylated cytosines in the reelin promoter region relative to untreated NT2 cells. The reduction of reelin promoter cytosine methylation by AZA is consistent with the hypothesis that decreasing methylation increases mRNA expression via a reduction in HDAC activity. Interestingly, the VPA-and TSA-induced reduction of reelin promoter cytosine methylation suggest that DNA demethylase activity is facilitated by histone deacetylase inhibition. The data suggest that HDACs which attenuate promoter methylation are candidates for a new generation of therapeutics in the treatment of schizophrenia.

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Accession: 035980545

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