Genome wide chromatin accessibility analysis reveals a role for CREB in retinal ganglion cells axon growth decline in development and regeneration after optic nerve injury [RNA-seq]

CNS neurons lose their ability to grow and regenerate axons during development. This is the case for Retinal Ganglion Cells (RGCs) in the retina, which transmit visual information to the brain via axons projecting into the optic nerve. RGCs are unable to regenerate their axon after injury, and start a degeneration process that leads to cell death and loss of vision. To identifying molecular mechanisms that increase regeneration of RGC and may offer new treatment strategies for patients with glaucoma or other types of optic neuropathies, we focused on the identification of transcription factors and chromatin accessible sites that are enriched in RGC during developmental stages, in which axon growth capacity is robust. We find that stage-specific gene expression changes are correlated with temporal changes in promoter chromatin accessibility. We also find that Creb binding motifs are enriched in the differentially opened regions of the chromatin at embryonic developmental stage. Overexpression of active Creb promotes axon regeneration after optic nerve injury. Our results provide a map of the chromatin accessibility during RGC development and highlights that manipulating TF associated with developmental stages can stimulate axon growth in adulthood.中枢神经系统（Central Nervous System, CNS）神经元在发育过程中会丧失轴突生长与再生的能力。视网膜神经节细胞（Retinal Ganglion Cells, RGCs）正是此类神经元的代表：它们通过轴突投射进入视神经，将视觉信息传递至大脑。RGC在损伤后无法再生轴突，并会启动退行性病变进程，最终导致细胞死亡与视力丧失。为了阐明能够增强RGC再生能力的分子机制，为青光眼或其他类型视神经病变患者提供全新治疗策略，本研究聚焦于鉴定发育阶段（此时轴突生长能力旺盛）中RGC内富集的转录因子与染色质开放位点。我们发现，阶段特异性基因表达变化与启动子区域染色质可及性的时序变化显著相关。此外，我们还发现，在胚胎发育阶段，Creb结合基序在染色质差异开放区域中显著富集。活性Creb的过表达可促进视神经损伤后的轴突再生。本研究绘制了RGC发育过程中的染色质可及性图谱，并揭示：调控与发育阶段相关的转录因子（Transcription Factor, TF），可在成年个体中刺激轴突生长。