Epigenetic Regulation of Sensory Axon Regeneration after Spinal Cord Injury

The Journal of Neuroscience, 2013 · DOI: 10.1523/JNEUROSCI.0589-13.2013 · Published: December 11, 2013

Simple Explanation

Mature nerve cells in the central nervous system don't regenerate well. When the spinal cord is injured, messages between the brain and body are cut off, leading to loss of movement and feeling. A key reason for this is that nerve cells lose their ability to grow back as they mature. This study found that a process called histone acetylation, which affects how genes are turned on and off, is linked to the ability of nerve cells to regrow. When nerve cells are stimulated to grow, this acetylation process is restored, and genes that help with regeneration are activated. The researchers also discovered that by using drugs to control histone modification, they could activate these regeneration genes and encourage the regrowth of sensory nerve fibers in a mouse model of spinal cord injury, suggesting a potential new way to treat such injuries.

Study Duration

2 weeks

Participants

C57BL/6 female mice, CD1 mice, Smad1flox/flox mice, Wnt1-Cre line

Evidence Level

Not specified

Key Findings

1
Diminished axon growth potential correlates with histone 4 (H4) hypoacetylation in mature DRG neurons.
2
Targeted pharmacological modulation of histone deacetylases leads to induction of multiple regeneration-associated genes.
3
Systemic administration of HDAC inhibitors promotes sensory axon regeneration after spinal cord injury in mice.

Research Summary

The study establishes a correlation between diminished axon growth potential and histone 4 (H4) hypoacetylation in mature dorsal root ganglion (DRG) neurons. It identifies a transcriptional complex involving pSmad1 and histone-modifying enzymes that restores promoter histone acetylation and induces a subset of early regeneration-associated genes (RAGs). Targeted pharmacological modulation of histone deacetylases in vivo leads to histone H4 hyperacetylation, induction of multiple RAGs, and promotion of sensory axon regeneration after spinal cord injury.

Practical Implications

Therapeutic Potential

Epigenetic modulation may be a potential therapeutic strategy to enhance axon regeneration after spinal cord injury.

Drug Development

Targeting HDACs with specific inhibitors like MS-275 could promote axon regeneration.

Combinatorial Therapy

Combining epigenetic modulation with activation of pro-regenerative signaling pathways (e.g., BMP/Smad1) may lead to greater axonal regeneration.

Study Limitations

1
The in vivo promoting effect of MS-275 remains modest with the current treatment regimen.
2
Systemic administration of TSA or MS-275 may affect non-neuronal cells, such as glia, which may provide trophic support to promote regeneration.
3
The study cannot rule out the possibility that TSA or MS-275 treatment inhibits the activity of HDACs in deacetylating cytoplasmic proteins.

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