RGD Reference Report - HDAC inhibition promotes neuronal outgrowth and counteracts growth cone collapse through CBP/p300 and P/CAF-dependent p53 acetylation. - Rat Genome Database

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HDAC inhibition promotes neuronal outgrowth and counteracts growth cone collapse through CBP/p300 and P/CAF-dependent p53 acetylation.

Authors: Gaub, P  Tedeschi, A  Puttagunta, R  Nguyen, T  Schmandke, A  Di Giovanni, S 
Citation: Gaub P, etal., Cell Death Differ. 2010 Sep;17(9):1392-408. doi: 10.1038/cdd.2009.216. Epub 2010 Jan 22.
RGD ID: 7364756
Pubmed: PMID:20094059   (View Abstract at PubMed)
DOI: DOI:10.1038/cdd.2009.216   (Journal Full-text)

Neuronal outgrowth is guided by both extrinsic and intrinsic factors, involving transcriptional regulation. The acetylation of histones and transcription factors, which facilitates promoter accessibility, ultimately promotes transcription, and depends on the balance between histone deacetylases (HDACs) and histone acetyltransferases (HATs) activities. However, a critical function for specific acetylation modifying enzymes in neuronal outgrowth has yet to be investigated. To address this issue, we have used an epigenetic approach to facilitate gene expression in neurons, by using specific HDAC inhibitors. Neurons treated with a combination of HDAC and transcription inhibitors display an acetylation and transcription-dependent increase in outgrowth and a reduction in growth cone collapse on both 'permissive' (poly-D-lysine, PDL) and 'non-permissive' substrates (myelin and chondroitin sulphate proteoglycans (CSPGs)). Next, we specifically show that the expression of the histone acetyltransferases CBP/p300 and P/CAF is repressed in neurons by inhibitory substrates, whereas it is triggered by HDAC inhibition on both permissive and inhibitory conditions. Gene silencing and gain of function experiments show that CBP/p300 and P/CAF are key players in neuronal outgrowth, acetylate histone H3 at K9-14 and the transcription factor p53, thereby initiating a pro-neuronal outgrowth transcriptional program. These findings contribute to the growing understanding of transcriptional regulation in neuronal outgrowth and may lay the molecular groundwork for the promotion of axonal regeneration after injury.



Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Ep300Ratcellular response to trichostatin A  IEP  RGD 
Kat2bRatpositive regulation of neuron projection development  IMP  RGD 

Objects Annotated

Genes (Rattus norvegicus)
Ep300  (E1A binding protein p300)
Kat2b  (lysine acetyltransferase 2B)


Additional Information