Silencing of Fem1c R3 gene expression in the DBA/2J mouse precedes retinal ganglion cell death and is associated with histone deacetylase activity

Heather R. Pelzel, Cassandra L. Schlamp, Michael Waclawski, Malissa K. Shaw, Robert W. Nickells

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

PURPOSE. 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. METHODS. 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). RESULTS. 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. CONCLUSIONS. 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.

Original languageEnglish
Pages (from-to)1428-1435
Number of pages8
JournalInvestigative Ophthalmology and Visual Science
Volume53
Issue number3
DOIs
Publication statusPublished - Mar 1 2012
Externally publishedYes

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Inbred DBA Mouse
Histone Deacetylases
Retinal Ganglion Cells
trichostatin A
Histone Deacetylase Inhibitors
Cell Death
Acetylation
Gene Expression
Ganglia
Alleles
Nerve Degeneration
Optic Nerve Diseases
Cell Aging
Gene Silencing
Optic Nerve
Reporter Genes
Epigenomics
Glaucoma
Histones
Chromatin

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience

Cite this

Silencing of Fem1c R3 gene expression in the DBA/2J mouse precedes retinal ganglion cell death and is associated with histone deacetylase activity. / Pelzel, Heather R.; Schlamp, Cassandra L.; Waclawski, Michael; Shaw, Malissa K.; Nickells, Robert W.

In: Investigative Ophthalmology and Visual Science, Vol. 53, No. 3, 01.03.2012, p. 1428-1435.

Research output: Contribution to journalArticle

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abstract = "PURPOSE. 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. METHODS. 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). RESULTS. 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. CONCLUSIONS. 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.",
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N2 - PURPOSE. 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. METHODS. 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). RESULTS. 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. CONCLUSIONS. 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.

AB - PURPOSE. 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. METHODS. 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). RESULTS. 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. CONCLUSIONS. 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.

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