Developmental chromatin restriction of pro-growth gene networks acts as an epigenetic barrier to axon regeneration in cortical neurons

Dev Neurobiol, 2018 · DOI: 10.1002/dneu.22605 · Published: October 1, 2018

Simple Explanation

The study investigates why central nervous system (CNS) neurons lose their ability to regenerate axons as they mature. It suggests that changes in how DNA is packaged (chromatin accessibility) might be a reason. The researchers used a computer-based approach to analyze gene activity, transcription factor regulation, and chromatin accessibility in developing cortical neurons. The findings indicate that as neurons mature, the chromatin around genes associated with axon growth becomes less accessible, potentially hindering regeneration. Identifying 'pioneer factors' may help reverse this.

Study Duration

Not specified

Participants

Adult female C57/Bl6 mice (>8wks age, 20–22g)

Evidence Level

Not specified

Key Findings

1
Overall closure of chromatin in sub-networks of genes associated with axon growth was detected in the developing cortex.
2
Chromatin accessibility in JUN or STAT3 target genes was substantially lower than in predicted targets of SOX11 and KLF7.
3
The study predicted pioneer factors that could potentially relieve chromatin constraints at growth-associated loci.

Research Summary

This integrated analysis substantiates the hypothesis that dynamic chromatin accessibility contributes to the developmental decline in axon growth ability and influences the efficacy of pro-regenerative interventions in the adult, while also pointing toward selected pioneer factors as high-priority candidates for future combinatorial experiments. Genes that change in expression as neurons mature, and identify functional gene networks, both positive and negative, that may influence the developmental decline in axon growth ability. Cortical maturation is associated with a selective reduction of chromatin accessibility in genes associated with axon extension, suggesting a role for chromatin accessibility in restricting axon growth in the adult CNS.

Practical Implications

Targeted Therapies

Identifying pioneer factors could lead to more targeted therapies that promote axon regeneration by opening up chromatin at specific gene loci.

Combination Therapies

Combining pro-regenerative transcription factors with pioneer factors may enhance the efficacy of regeneration strategies in the adult CNS.

Pre-screening TFs

Promoter accessibility of target genes could be used as an early indicator of potential efficacy for future candidate TFs.

Study Limitations

1
Discrepancies in tissue type, age, and data processing of input data.
2
The 3D spatial organization of the accessible genome is increasingly appreciated as critical regulatory mechanism, and can probed with emerging technologies such as ATAC-see. This concept remains unexplored in regenerative neuroscience, but may also yield critical insights
3
The tools presented here would be powered by unified datasets from purified CST neurons of early postnatal and adult ages. Owing to the technical challenges of obtaining such source material, and the relative nascence of attention to these approaches in the regeneration field, these ideal datasets are unavailable or in development.

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