Silencing ofFem1cR3Gene Expression in the DBA/2J Mouse Precedes Retinal Ganglion Cell Death and Is Associated with Histone Deacetylase Activity
Copyright policy )Silencing ofFem1cR3Gene Expression in the DBA/2J Mouse Precedes Retinal Ganglion Cell Death and Is Associated with Histone Deacetylase Activity
Downregulation of normal gene expression in dying retinal ganglion cells has been documented in both acute and chronic models of optic nerve disease. The authors examined the mechanism and timing of this phenomenon in DBA/2J mice, using genetically modified substrains of this inbred line.DBA/2J mice, doubly congenic for the Bax mutant allele and the ganglion cell reporter gene Fem1c(Rosa3) (R3), were evaluated to elucidate the timing of loss of normal gene expression during the apoptotic process. The localization of histone deacetylase 3 (HDAC3) and nuclear histone H4 acetylation were examined by immunofluorescence in dying cells. The role of HDACs in gene silencing during glaucoma was interrogated using the global HDAC inhibitor trichostatin A (TSA).Silencing of the R3 allele occurred in Bax(-/-) ganglion cells, indicating that this process preceded the committed step of the intrinsic apoptotic pathway. Weekly TSA treatment, between the ages of 6 and 10 months, was able to attenuate the loss of R3 expression in the retina, but had no effect on optic nerve degeneration. Dying cells in aging DBA/2J mice exhibited nuclear localization of HDAC3 and a decrease in the level of H4 acetylation.Retinal ganglion cells exhibit a loss of normal gene expression as an early (pre-BAX involvement) part of their apoptotic program during glaucomatous degeneration. This process can be ameliorated, but not completely blocked, using HDAC inhibitors. Epigenetic changes to active chromatin, such as deacetylation, may be mediated by HDAC3 in dying neurons.
- University of Wisconsin System United States
- University of Wisconsin–Madison United States
- University of Wisconsin–Oshkosh United States
- University of Wisconsin–Whitewater United States
Retinal Ganglion Cells, Cell Death, Ubiquitin-Protein Ligase Complexes, Acetylation, Chromatin, Histone Deacetylases, DNA-Binding Proteins, Histone Deacetylase Inhibitors, Histones, Mice, Gene Expression Regulation, Genes, Reporter, Mice, Inbred DBA, Optic Nerve Diseases, Animals, Gene Silencing, Transcription Factors
Retinal Ganglion Cells, Cell Death, Ubiquitin-Protein Ligase Complexes, Acetylation, Chromatin, Histone Deacetylases, DNA-Binding Proteins, Histone Deacetylase Inhibitors, Histones, Mice, Gene Expression Regulation, Genes, Reporter, Mice, Inbred DBA, Optic Nerve Diseases, Animals, Gene Silencing, Transcription Factors
citations This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).54 popularity This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.Top 10% influence This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).Top 10% impulse This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.Top 10%
Citations provided by BIP!Popularity provided by BIP!