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

Injury induces retinal Muller glia of cold-blooded, but not mammalian, vertebrates to generate neurons. To identify gene regulatory networks that control neurogenic competence 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. Integration of these data, together with functional analysis of candidate genes, identified evolutionarily conserved and species-specific gene networks controlling glial quiescence, gliosis, and neurogenic competence. 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 in mice, which maintain and restore quiescence, confers injury-dependent proliferative and neurogenic competence on Muller glia. These findings may help guide the design of cell-based therapies aimed at restoring retinal neurons lost in disease.