Advances and Limitations of Current Epigenetic Studies Investigating Mammalian Axonal Regeneration

Injury to the nervous system, such as following traumatic spinal cord and brain injuries, or a vascular insult such as stroke, causes loss of neuronal function leading to sensory, motor, autonomic or cognitive impairment. Successful compensatory axonal sprouting from intact neurons or regeneration from injured axons, i.e. regrowth of the injured axon to the original target is required for functional recovery. In mammals, axonal regeneration relies on the synergy between the presence of a permissive extracellular environment and the intrinsic growth capacity of the injured neurons [ 1 , 2 , 3 ]. While the mammalian peripheral nervous system (PNS) axons are able to regenerate to a certain extent, axons in the central nervous system (CNS) do not, due to the presence of glial inhibitory signalling, glial scar and to a limited neuronal intrinsic regenerative ability [ 4 , 5 , 6 ]. Interference with the inhibitory glial extra-neuronal cues has resulted into an improvement of axonal regrowth in the injured CNS [ 7 , 8 , 9 ]. However, this remains rather limited, and it has prompted the development of strategies aimed to enhance the poor neuronal intrinsic growth ability. While protein translation seems to play a role (reviewed elsewhere [ 10 , 11 ]), the axon growth competence of neurons in both the PNS and CNS depends mainly on gene transcription, and on the capability to initiate an orchestrated transcriptional response to injury [ 12 ]. This ability declines during neuronal maturation and with aging [ 13 , 14 , 15 , 16 , 17 ]. The decline in regenerative ability is mainly due to changes in the transcriptional programme, which is affected by an overall reduction in chromatin accessibility at gene regulatory regions as a function of development. This is associated with a drop in the level of transcription factors (TFs) and in the transcription of genes needed for axonal regeneration [ 18 , 19 ], and it might explain why forced expression of TFs or regeneration associated genes (RAGs) [ 20 ], alone or in combination, has resulted in limited axonal regeneration so far [ 21 , 22 , 23 ]. Although some experiments are biased by the heterogeneity of the nervous system tissue, there is evidence that expression of epigenetic modifiers and epigenetic marks are regulated during development. For example, immunoblotting of H3K9/14ac from cortical and cerebellar granule neuron (CGN) extracts [ 24 ] as well as H3K18ac and p300 immunostaining in retinal ganglia neurons (RGNs) [ 25 ] has revealed a decrease in the expression of these positive epigenetic marks in mature compared to earlier developmental stages. A chromatin immunoprecipitation small screening of histone post-translational modifications (HPTM) in cortical neurons revealed pronounced changes in histone marks at the promoter regions of several RAGs, indicative of progressive reduced chromatin accessibility during post-natal development [ 19 ].