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

Simone Di Giovanni (1) , Perrine Gaub (1) , Andrea Tedeschi (1) , Radhika Puttagunta (1) , Tuan Huy Nguyen (1) , Antonio Schmandke (1)

1 Neurology

Neuronal outgrowth is guided by both extrinsic and intrinsic factors, involving transcriptional regulation. The acetylation of histones and transcription factors, which facilitates promoters' accessibility, ultimately promotes transcription, and depends upon the balance between histone deacetylases and histone acetyltransferases activities. However, a critical role for specific acetylation modifying enzymes in neuronal outgrowth has yet to be investigated. To address this issue, we have employed an epigenetic approach to facilitate gene expression in neurons, by using specific histone deacetylase (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) and "non-permissive" substrates (myelin and CSPGs). Next, we specifically demonstrate that the expression of the histone acetyltransferases CBP/p300 and P/CAF is repressed in neurons by inhibitory substrates, while 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 following injury.

Mots clés: CBP; P/CAF; acetylation; neuronal outgrowth; p53

Simone Di Giovanni, Perrine Gaub, Andrea Tedeschi, Radhika Puttagunta, Tuan Huy Nguyen, et al.. HDAC inhibition promotes neuronal outgrowth and counteracts growth cone collapse through CBP/p300 and P/CAF-dependent p53 acetylation. Cell Death and Differentiation, 2010, n/a (n/a), pp.n/a-n/a. ⟨10.1038/cdd.2009.216⟩. ⟨hal-00504936⟩