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

By Thanh Hoang, Jie Wang, Patrick Boyd, Fang Wang, Clayton Santiago, Lizhi Jiang, Manuela Lahne, Sooyeon Yoo, Levi J. Todd, Cristian Saez, Casey Keuthan, Isabella Palazzo, Natalie Squires, Warren J Campbell, Meng Jia, Fatemeh Rajaii, Trisha Parayil, Vickie Trinh, Dong Won Kim, Guohua Wang, John Ash, Andy J Fischer, David R Hyde, Jiang Qian, Seth Blackshaw

Posted 30 Jul 2019
bioRxiv DOI: 10.1101/717876

Injury induces retinal Müller glia of cold-blooded, but not mammalian, vertebrates to regenerate neurons. To identify gene regulatory networks that control neuronal reprogramming in retinal glia, we comprehensively profiled injury-dependent changes in gene expression and chromatin accessibility in Müller glia from zebrafish, chick and mice using bulk RNA-Seq and ATAC-Seq, as well as single-cell RNA-Seq. Cross-species integrative analysis of these data, together with functional validation, identified evolutionarily conserved and species-specific gene networks controlling glial quiescence, gliosis and neurogenesis. In zebrafish and chick, transition from the resting state to gliosis is essential for initiation of retinal regeneration, while in mice a dedicated network suppresses neurogenic competence and restores quiescence. Selective disruption of NFI family transcription factors, which maintain and restore quiescence, enables Müller glia to proliferate and generate neurons in adult mice following retinal injury. These findings may aid in the design of cell-based therapies aimed at restoring retinal neurons lost to degenerative disease. Summary sentence This study identifies gene regulatory networks controlling proliferative and neurogenic competence in retinal Müller glia.

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