title: The histone acetyltransferase p300 promotes intrinsic axonal regeneration.
abstract: 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.
authors.affiliation: Centre for Neurology, Laboratory for NeuroRegeneration and Repair, Hertie Institute for Clinical Brain Research, University of Tübingen, Otfried-Mueller Strasse 27, Tübingen, Germany.
authors.forename: Perrine
authors.initials: P
authors.lastname: Gaub
authors.forename: Yashashree
authors.initials: Y
authors.lastname: Joshi
authors.forename: Anja
authors.initials: A
authors.lastname: Wuttke
authors.forename: Ulrike
authors.initials: U
authors.lastname: Naumann
authors.forename: Sven
authors.initials: S
authors.lastname: Schnichels
authors.forename: Peter
authors.initials: P
authors.lastname: Heiduschka
authors.forename: Simone
authors.initials: S
authors.lastname: Di Giovanni
mesh_terms: D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D002352:Carrier Proteins / Q000378:metabolism; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D004195:Disease Models, Animal; D019922:GAP-43 Protein / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D049452:Green Fluorescent Proteins / Q000235:genetics; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006877:Hydroxamic Acids / Q000494:pharmacology; D066298:In Vitro Techniques; D009409:Nerve Crush / Q000379:methods; D009410:Nerve Degeneration / Q000209:etiology / Q000628:therapy*; D009416:Nerve Regeneration / Q000235:genetics* / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D016501:Neurites / Q000187:drug effects; D020221:Optic Nerve Injuries / Q000150:complications; D051381:Rats; D012160:Retina / Q000166:cytology; D012165:Retinal Ganglion Cells / Q000166:cytology / Q000187:drug effects; D014162:Transfection / Q000379:methods; D014404:Tubulin / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D050880:p300-CBP Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000099224:p300-CBP-Associated Factor
chemical_list: D002352:Carrier Proteins; D019922:GAP-43 Protein; D049452:Green Fluorescent Proteins; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D009419:Nerve Tissue Proteins; D014404:Tubulin; D016159:Tumor Suppressor Protein p53; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C488416:Tubb3 protein, rat; C020723:citrate-binding transport protein; C012589:trichostatin A