Abstract
Retinal Ganglion Cells (RGCs) lose their ability to grow axons during development. Adult RGCs thus fail to regenerate their axons after injury, leading to vision loss. To uncover mechanisms that promote regeneration of RGC axons, we identified transcription factors (TF) and open chromatin regions that are enriched in rat embryonic RGCs (high axon growth capacity) compared to postnatal RGCs (low axon growth capacity). We found that developmental stage-specific gene expression changes correlated with changes in promoter chromatin accessibility. Binding motifs for TFs such as CREB, CTCF, JUN and YY1 were enriched in the regions of the chromatin that were more accessible in embryonic RGCs. Proteomic analysis of purified rat RGC nuclei confirmed the expression of TFs with potential role in axon growth such as CREB, CTCF, YY1, and JUND. The CREB/ATF binding motif was widespread at the open chromatin region of known pro-regenerative TFs, supporting a role of CREB in regulating axon regeneration. Consistently, overexpression of CREB fused to the VP64 transactivation domain in mouse RGCs promoted axon regeneration after optic nerve injury. Our study provides a map of the chromatin accessibility during RGC development and highlights that TF associated with developmental axon growth can stimulate axon regeneration in mature RGC.
Highlights
Retinal Ganglion Cells (RGCs) lose their ability to grow axons during development
We have shown that the RNA expression of genes that control axon growth and ribosome biogenesis are downregulated during RGC development, and that the mRNA expression changes correlate with chromatin accessibility changes at the promoter region
We observed transcription factors (TF) whose target regions are becoming less accessible during RGC development including TFs with known roles in axon regeneration, such as CREB, JUN, SOX4, c-MYC, CTCF and HIF15,8,14,20,45–47, as well as other TFs whose roles in axon regeneration have not been thoroughly studied such as YY1, NRF1 and RFX
Summary
Retinal Ganglion Cells (RGCs) lose their ability to grow axons during development. Adult RGCs fail to regenerate their axons after injury, leading to vision loss. Binding motifs for TFs such as CREB, CTCF, JUN and YY1 were enriched in the regions of the chromatin that were more accessible in embryonic RGCs. Proteomic analysis of purified rat RGC nuclei confirmed the expression of TFs with potential role in axon growth such as CREB, CTCF, YY1, and JUND. Our study provides a map of the chromatin accessibility during RGC development and highlights that TF associated with developmental axon growth can stimulate axon regeneration in mature RGC. CREB binding sites were significantly enriched in the open chromatin regions specific to the E21 RGCs. Overexpressing CREB fused to a VP64 transactivation domain in RGCs induced axon regeneration after optic nerve injury, mimicking the axon growth capacity of embryonic neurons. Our data provides a road map of the chromatin accessibility during RGC development and highlights that manipulating TFs associated with developmental stages with high growth potential can stimulate axon growth in adulthood
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