Gene silencing in apoptotic retinal ganglion cells is associated with promoter histone deacetylation and nuclear translocation of HDAC3

One of the first events in neuronal apoptosis is the silencing of normal gene expression. Although this phenomenon has been well documented in several models of neurodegeneration, little work has been done to examine the mechanism responsible for this widespread downregulation.;There are several types of epigenetic changes that compose the histone code. One epigenetic change often associated with gene silencing is histone deacetylation. The central nervous system neurons, retinal ganglion cells (RGCs), undergo significant decreases in histone acetylation, as well as increases in histone deacetylase (HDAC) activity during apoptosis. These changes begin as early as 1 day post optic nerve crush (ONC) and peak at 5 days post ONC, which is prior to apoptotic cell loss. In addition, there is a sustained increase in the transcript level of Hdac3 followed by the nuclear translocation of HDAC3.;When trichostatin A (TSA), a general HDAC inhibitor, was used to treat RGCs prior to ONC, apoptotic silencing of at least one RGC-specific gene, Fem1c, was prevented. Moreover, the application of TSA was able to attenuate apoptotic loss of RGCs at 2 weeks post ONC.;In addition, similar changes in histone deacetylation and HDAC3 cellular localization were seen in RGCs from mice that develop a chronic glaucomatous condition. Thus, these changes appear to be related to the apoptotic process and are not an aritfact of the crush procedure.