Effects of histone deacetylase inhibitor Trichostatin A on epigenetic changes and transcriptional activation of Bdnf promoter 1 by rat hippocampal neurons.

Histone acetylation/deacetylation is a central mechanism for regulating transcription through chromatin remodeling. The brain-derived neurotrophic factor gene (Bdnf) is regulated in part through chromatin remodeling. An inhibitor of histone deacetylase (HDAC) activity, Trichostatin A (TSA), has differential effects on two activation dependent regions of the Bdnf gene physically linked to transcription sites for exons 1 and 4. We determined that TSA treatment of cultures of hippocampal neurons produced a stronger response at promoter 1. Transcriptional activation of promoter 1 correlated with increased occupancy of the promoter by acetylated histones (H3AcK9/K14). TSA treatment also produced a time-dependent increase in the level of H3AcK9 and H3AcK14 protein and Hdac1 mRNA levels and HDAC1 protein levels. Taken together, these findings suggest that inhibition of HDAC activity by TSA activates Bdnf transcription and a compensatory change in HDAC1 expression in neurons. This response may reflect a genome-wide change in gene expression.