The effect of Jun dimerization on neurite outgrowth and motif binding

Mol Cell Neurosci, 2018 · DOI: 10.1016/j.mcn.2018.08.001 · Published: October 1, 2018

Regenerative Medicine Neurology Genetics

Simple Explanation

Axon regeneration is crucial for recovery after spinal cord injury, and the AP-1 transcription factor c-Jun plays a vital role in this process. This study investigates how Jun's DNA binding changes in response to peripheral axotomy, particularly focusing on enhancer elements rather than transcription start sites. The research also examines the impact of different Jun-containing dimers on neurite outgrowth in various neuron types. Notably, dimers of Jun and Atf3 promote neurite outgrowth in both rat CNS and mouse DRG neurons. These findings offer new insights into the mechanisms by which Jun influences axon regeneration, highlighting the importance of enhancer elements and specific dimerization partners.

Study Duration

Not specified

Participants

Male C57BL/6 mice aged 6 to 8 weeks, Postnatal day 3 Sprague-Dawley rat pups, Embryonic day 18 Sprague-Dawley rat pups

Evidence Level

Not specified

Key Findings

1
The majority of Jun's injury-responsive changes in DNA binding occur at putative enhancer elements, not proximal to transcription start sites.
2
Dimers composed of Jun and Atf3 promoted neurite outgrowth in rat CNS neurons as well as mouse DRG neurons.
3
Jun~Atf3 is the only dimer tested in our studies that consistently promoted neurite outgrowth.

Research Summary

This study investigates the genomic locations bound by Jun in DRG neurons following a peripheral axotomy, observing that the majority of Jun’s injury-responsive binding sites are on putative enhancer elements, while the majority of its injury-invariant binding sites are on promoter elements. The research tests the sufficiency of single polypeptide chain Jun-containing dimers to promote neurite outgrowth of DRG, cortical and hippocampal neurons in vitro, finding that Jun dimers with Fos and Jun family members are expected to bind the TRE motif, while Jun dimers with Atf family members are expected to bind the CRE motif. The differential binding results from ChIPseq data support the hypothesis that Jun binding activity is increased after peripheral axotomy and the majority of changes in Jun activity after peripheral axotomy occur at enhancers rather than at promoters.

Practical Implications

Enhancer Target Identification

These ChIPseq data will help to reveal which genes Jun is regulating through distal binding sites once chromatin conformation data in these biological conditions becomes available.

Targeted Therapeutic Development

Overexpression of Jun~Atf3 tethered dimers might more effectively promote axon regeneration in vivo than overexpressing a mixture of the two monomers.

Dimerization State Manipulation

Injured CNS neurons may not be in the appropriate signaling state to allow Jun and Atf3 to dimerize productively. Future research should explore how to manipulate this signaling to enhance dimerization and promote regeneration.

Study Limitations

1
Lack of concordance between increases in Jun binding near promoters and increases in gene expression after injury.
2
The majority of post-injury binding sites had either TRE, CRE or no recognizable Jun-related motif – exactly the same as before injury.
3
This work does not examine the effects of dimers containing Atf, Fos or other Jun family members without Jun itself.

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