Histone and DNA methyltransferases in optic nerve regeneration

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Project summary Mature neurons in the central nervous system of adult mammals, including retinal ganglion cells (RGCs) whose axons form the optic nerve, are incapable of regenerating. This presents a major challenge to restoring vision in patients with optic nerve injury or diseases, such as glaucoma, an optic nerve disease that affects 80 million people globally. Long-standing works from my laboratory demonstrate that optic nerve elongation is a programed event during development whose shut-down contributes critically to the failure of optic nerve regeneration. Potentially, epigenetic modification may reprogram neurons to regain this capacity by reactivating progenitor cell genes that have been silenced during neural maturation. Methylation, a key epigenetic mechanism carried out by histone methyltransferases (HMTs) and DNA methyltransferases (DNMTs), is essential in retinogenesis. Increased levels of methylation and methyltransferases activity is highly correlated with aging and retinal diseases progression. However, the functional role of epigenetic factors HMTs and DNMTs in RGC degeneration, or glaucoma in general, is unclear. By examining specific epigenetic changes associated with RGCs in mouse, we recently detected dynamic expression of a major HMT, enhancer of zeste homolog 1 (Ezh1) and a key member of DNMTs, that inversely correlate with retinal neuritogenesis and the optic nerve regenerative capacity of RGCs. Importantly, our pilot study found that pan inhibition of Ezh1 or DNMTs by small-molecule compounds increased neurite outgrowth in primary RGCs in vitro, and mice carrying selective DNMT deficiency in RGCs promoted robust axon re-growth in vitro and in injured optic nerve in vivo. We hypothesized that resetting the developmental epigenetic program induced by Ezh1 or DNMTs promotes the regenerative capacity of the optic nerve. The hypothesis will be tested in two specific aims: (1) Exploit the molecular events by which Ezh1 and DNMTs regulate RGC neurite growth in vitro, and (2) Examine the role of Ezh1 or DNMTs in optic nerve growth in vivo. This study will advance our knowledge about the epigenetic modulation of neuritogenesis, with the potential of discovering novel therapeutic strategies against neurodegenerative diseases.