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

摘要

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 Hdacl mRNA levels and HDAC I protein levels. Taken together, these findings suggest that inhibition of HDAC activity by TSA activates Bdnf transcription and a compensatory change in HDAC 1 expression in neurons. This response may reflect a genome-wide change in gene expression.