Cross-species transcriptomic and epigenomic analysis reveals key regulators of injury response and neuronal regeneration in vertebrate retinas

Abstract Injury induces retinal Muller glia of cold-blooded, but not mammalian, vertebrates to generate neurons. To identify gene regulatory networks that control neuronal reprogramming in retinal glia, we comprehensively profiled injury-dependent changes in gene expression and chromatin conformation in Muller glia from zebrafish, chick and mice using bulk RNA and ATAC-Seq, as well as single-cell RNA-Seq. Cross-species integrative analysis of these data, together with functional validation of candidate genes, identified evolutionarily conserved and species-specific gene networks controlling glial quiescence, gliosis and neurogenesis. In zebrafish and chick, transition from quiescence to gliosis is a critical stage in acquisition of neurogenic competence, while in mice a dedicated network suppresses this transition and rapidly restores quiescence. Selective disruption of NFI family transcription factors, which maintain and restore quiescence, enables Muller glia to proliferate and robustly generate neurons in adult mice after retinal injury. These comprehensive resources and findings will facilitate the design of cell-based therapies aimed at restoring retinal neurons lost to degenerative disease.