Chromatin-modifying agents increase transcription of CYP46A1, a key player in brain cholesterol elimination.

摘要: The major mechanism of brain cholesterol elimination is the conversion into 24S-hydroxycholesterol by CYP46A1, a neuron-specific cytochrome P450. Since increasing evidence suggests that upregulation CYP46A1 may be relevant for treatment Alzheimer's disease, we aim to identify molecular mechanisms involved in transcription. Our previous studies demonstrated role Sp transcription factors basal expression and histone deacetylase (HDAC) inhibitor-dependent derepression CYP46A1. Here, show demethylating agent 5'-Aza-2'-deoxycytidine (DAC) inducer pre-treatment with DAC causes marked synergistic activation trichostatin A. Surprisingly, bisulfite sequencing analysis revealed core promoter completely unmethylated both human non-neuronal tissues where not expressed. Therefore, have investigated levels western blot real-time PCR, their binding patterns promoter, electrophoretic mobility shift assay chromatin immunoprecipitation assays, after treatment. results showed decreases only Sp1 Sp3 protein levels, but also activity +1 region locus. Concomitantly, HDAC1 HDAC2 were significantly dissociated from promoter. In conclusion, induces gene expression, DNA methylation-independent mechanism, decreasing Sp3/HDAC proximal Furthermore, affecting factor neuronal cells, might affect metabolism, many other genes.