Abstract
Neuroregenerative therapies for central nervous system (CNS) injury, neurodegenerative disease, or stroke require axons of damaged neurons to grow and re-innervate their targets. However, mature mammalian CNS neurons do not regenerate their axons, limiting recovery in these diseases. Although neurons' intrinsic capacity for axon growth may depend in part on the panoply of expressed transcription factors, epigenetic factors such as the accessibility of DNA and organization of chromatin are required for downstream genes to be transcribed. Thus, a potential approach to overcoming regenerative failure focuses on the epigenetic mechanisms regulating regenerative gene expression in the CNS. Here we review molecular mechanisms regulating the epigenetic state of DNA through chromatin modifications, their implications for regulating axon and dendrite growth, and important new directions for this field of study.
Highlights
Epigenetics is the regulation of gene expression beyond the heritable DNA sequence (Bird, 2007), by enzymes and their substrate modifications, which gate access to and transcription from DNA (Reik, 2007), and may play role in expression of regenerative genes in the nervous system
Because access to DNA through chromatin remodeling is required for transcription factors to transcribe their target genes, epigenetic mechanisms may play a significant role in regulating expression of pro-regenerative genes
Chromatin immunoprecipitation (ChIP) revealed that trichostatin A (TSA) increased H3K9/14 acetylation on CBP/p300 and P/CAF promoters, but not on a promoter of a control RPL13a gene (Gaub et al, 2010). These findings suggest that TSA induces promoter-specific histone 3 (H3) hyperacetylation, and that CBP/p300 and P/CAF are potential mediators of the TSA-induced increase and myelin-induced decrease in neurite growth, highlighting the importance of transcriptional regulation in neurite growth
Summary
Reviewed by: Simone Di Giovanni, University of Tuebingen, Germany Christina F. Neuroregenerative therapies for central nervous system (CNS) injury, neurodegenerative disease, or stroke require axons of damaged neurons to grow and re-innervate their targets. Mature mammalian CNS neurons do not regenerate their axons, limiting recovery in these diseases. Neurons’ intrinsic capacity for axon growth may depend in part on the panoply of expressed transcription factors, epigenetic factors such as the accessibility of DNA and organization of chromatin are required for downstream genes to be transcribed. A potential approach to overcoming regenerative failure focuses on the epigenetic mechanisms regulating regenerative gene expression in the CNS. We review molecular mechanisms regulating the epigenetic state of DNA through chromatin modifications, their implications for regulating axon and dendrite growth, and important new directions for this field of study
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