Epigenetic Control of Functional Axon Regeneration
Cassin, Jessica Bailey Walters
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The failure of central nervous system axons to regenerate is a known consequence of traumatic injury and neurodegenerative disease. The central nervous system’s regenerative capacity starkly contrasts with the peripheral nervous system, which demonstrates robust regeneration following injury. This ability is due to factors both extrinsic and intrinsic to the cell. Extrinsically, the environment of the central nervous system is inhospitable, presenting both physical and chemical barriers to regeneration. However, extrinsic factors are not the only component. When placed in a peripheral nervous context, central nervous system neurons still show only modest gains in regeneration. Intrinsically, the peripheral nervous system is able to upregulate genes known as regeneration associated genes which are important for the system’s ability to regenerate. These genes, when expressed in a central nervous system neuron can promote gains in regeneration, although not to the same extent as the peripheral nervous system. Despite an identical genetic complement, the central nervous system is unable to independently mobilize regeneration associated genes and promote regeneration. For this reason, we hypothesized that epigenetic differences between the central and peripheral nervous systems may be responsible. These epigenetic signatures are acquired by cells as they mature and differentiate. DNA methylation and chromatin structure are positioned so as to protect cell identity and allow expression of genes necessary for that cell’s function. Adult neurons must be tightly regulated. As such, many genes responsible for the growth and regeneration abilities seen in embryonic neurons are epigenetically silenced once the cell is fully differentiated. We show that Tet3, a DNA demethylase, is essential for regeneration in the PNS. In our model, Tet3 activates a suite of regeneration association genes necessary to initiate the regeneration program in the peripheral nervous system. Tet3 accomplishes this by selectively demethylating key regions of essential regeneration associated genes and allowing their expression. Without Tet3, the cell is unable to achieve functional regeneration. This study highlights the precise and delicate nature of regeneration in the peripheral nervous system and underscores the need for a holistic approach to activating regeneration in the central nervous system. Future studies will need to further refine the role of these dual highly regulated processes, transcription and translation, to unlock the regenerative potential of the central nervous system.