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.

A Small Molecule Activator of p300/CBP Histone Acetyltransferase Promotes Survival and Neurite Growth in a Cellular Model of Parkinson’s Disease

“…In support of our findings, p300/CBP has been shown to contribute to the survival, differentiation and neurite growth of a variety of neuronal cell types in the nervous system in vitro and in vivo (Chatterjee et al 2013;Chen et al 2010;Cong et al 2005;Culmsee et al 2003;Gaub et al 2011;Gaub et al 2010;Koyano-Nakagawa et al 1999;Lee et al 2009;Morikawa et al 2005;Rouaux et al 2003;Seo et al 2012;Sun et al 2001;Tsui et al 2014;Wang et al 2010;Wong et al 2005). In terms of the development of midbrain DA neurons, which progressively degenerate in PD, there is evidence to suggest that p300/CBP contributes to the acquisition of a DA phenotype in differentiating neurons (Seo et al 2012).…”

“…This is an important finding considering the limited number of HAT activators which have been produced (Schneider et al 2013), and the corresponding paucity of studies investigating their neurotrophic potential. The ability of p300/CBP activity to promote neurite growth has been reported in other neuronal populations (Gaub et al 2011;Gaub et al 2010;Lee et al 2009), while small molecule-mediated activation of p300/CBP promotes the growth of neurons in the adult mouse dentate gyrus in vivo (Chatterjee et al 2013). …”

PCAF-dependent epigenetic changes promote axonal regeneration in the central nervous system

“…While our work here describes that specific epigenetic codes are induced endogenously following a conditioning lesion that leads to CNS regeneration, it is also consistent with previous findings from our laboratory that showed the presence of a transcriptional complex formed by p53, p300 and PCAF in the proximity of several RAGs including GAP-43, Coronin 1b and Rab13 in primary neurones as well as facial motor neurones in a PNS facial nerve axotomy model [34][35][36] . Additionally, we found that the histone acetyltransferase p300 (which may form a complex with PCAF) is developmentally regulated in retinal ganglion cells and whose overexpression drives axonal regeneration of the injured optic nerve 33 .…”

“…It has been hypothesized that merely shifting the balance from a deacetylated to a globally acetylated chromatin environment by inhibition of HDACs could recapitulate the conditioning lesion and could lead to regeneration. However, recent experimental evidence 32 and our own work using HDAC class I and HDAC class I and II inhibitors 33 has proven this to be insufficient in producing postlesion regeneration of sensory fibres following a spinal or optic nerve injury and therefore unlikely the key to unlocking the molecular mechanisms of regeneration. While our work here describes that specific epigenetic codes are induced endogenously following a conditioning lesion that leads to CNS regeneration, it is also consistent with previous findings from our laboratory that showed the presence of a transcriptional complex formed by p53, p300 and PCAF in the proximity of several RAGs including GAP-43, Coronin 1b and Rab13 in primary neurones as well as facial motor neurones in a PNS facial nerve axotomy model [34][35][36] .…”

Tip off the HAT– Epigenetic control of learning and memory byDrosophilaTip60

“…For example, CBP was shown to ameliorate learning and memory deficits in a mouse AD model by increasing brain derived neurotropic factor (BDNF) 38 while p300 but not HDAC inhibitors was found to promote axonal regeneration by inducing axonal outgrowth genes. 83 It is important to consider that modulation of specific HAT levels and/or activity might epigenetically reprogram multiple specific genes that function together to produce a neuroprotective effect, as suggested by our ChIP-Seq analysis for Tip60. 7,34 Therefore, it will be critical to identity the full array of these genes to further dissect their neuroprotective nature for more effective design of specific HAT based therapeutic strategies.…”