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The histone acetyltransferase p300 promotes intrinsic axonal regeneration

Perrine Gaub, Yashashree Joshi, Anja Wuttke, Ulrike Naumann, Sven Schnichels, Peter Heiduschka, Simone Di Giovanni
DOI: http://dx.doi.org/10.1093/brain/awr142 2134-2148 First published online: 24 June 2011

Summary

Axonal regeneration and related functional recovery following axonal injury in the adult central nervous system are extremely limited, due to a lack of neuronal intrinsic competence and the presence of extrinsic inhibitory signals. As opposed to what occurs during nervous system development, a weak proregenerative gene expression programme contributes to the limited intrinsic capacity of adult injured central nervous system axons to regenerate. Here we show, in an optic nerve crush model of axonal injury, that adenoviral (cytomegalovirus promoter) overexpression of the acetyltransferase p300, which is regulated during retinal ganglion cell maturation and repressed in the adult, can promote axonal regeneration of the optic nerve beyond 0.5 mm. p300 acetylates histone H3 and the proregenerative transcription factors p53 and CCAAT-enhancer binding proteins in retinal ganglia cells. In addition, it directly occupies and acetylates the promoters of the growth-associated protein-43, coronin 1 b and Sprr1a and drives the gene expression programme of several regeneration-associated genes. On the contrary, overall increase in cellular acetylation using the histone deacetylase inhibitor trichostatin A, enhances retinal ganglion cell survival but not axonal regeneration after optic nerve crush. Therefore, p300 targets both the epigenome and transcription to unlock a post-injury silent gene expression programme that would support axonal regeneration.

  • p300
  • histone acetyltransferase
  • optic nerve
  • axonal regeneration
  • transcription
  • Abbreviations
    AVGFP
    adenovirus green fluorescent protein
    CBP
    cyclic adenosine monophosphate responsive element binding protein
    C/EBP
    CCAAT-enhancer binding protein
    GFP
    green fluorescent protein
    P/CAF
    p300/CBP-associated factor
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