Histone and DNA methyltransferases in optic nerve regeneration

项目摘要 成年哺乳动物中枢神经系统中的成熟神经元，包括视网膜神经节细胞（RGC），其 形成视神经的轴突不能再生这对恢复视力提出了重大挑战， 视神经损伤或疾病患者，如青光眼，一种影响8000万人的视神经疾病 全球的人。我实验室的长期工作表明，视神经的延长是一个程序性的， 在发育过程中发生的事件，其关闭对视神经再生的失败至关重要。 潜在地，表观遗传修饰可以通过重新激活祖细胞来重新编程神经元以恢复这种能力。 在神经成熟过程中沉默的基因。甲基化，一个关键的表观遗传机制， 通过组蛋白甲基转移酶（HMT）和DNA甲基转移酶（DNMT），在视网膜发生中是必需的。 甲基化水平和甲基转移酶活性的增加与衰老和视网膜病变高度相关。 疾病进展。然而，表观遗传因子HMTs和DNMTs在RGC中的功能作用 变性，或青光眼一般，是不清楚的。通过检查与以下疾病相关的特定表观遗传变化， 在小鼠RGCs中，我们最近检测到一种主要的HMT，zeste增强子同源物1（Ezh1）的动态表达。 是DNMTs的关键成员，与视网膜神经突发生和视神经再生呈负相关， RGC的能力。重要的是，我们的初步研究发现，小分子药物对Ezh1或DNMT的泛抑制作用 化合物增加体外原代RGCs和携带选择性DNMT缺陷的小鼠的神经突生长， 在RGC中，在体外和在体内损伤的视神经中促进了稳健的轴突再生长。我们假设 重置Ezh1或DNMT诱导的发育表观遗传程序促进再生能力 视神经这一假说将在两个具体的目标进行测试：（1）利用分子事件， Ezh1和DNMTs在体外调节RGC神经突起的生长，（2）检查Ezh1或DNMTs在视神经生长中的作用。 体内神经生长这项研究将推进我们对轴突发生的表观遗传调节的认识， 具有发现针对神经退行性疾病的新治疗策略的潜力。

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.