2022 Annual Meeting and Alumni Reunion
Category : Basic and Translational Research Candidate : Feng Tian Poster #: B21
Core Transcription Programs Controlling Injury-Induced Neurodegeneration of Retinal Ganglion Cells
Feng Tian , Yuyan Cheng , Songlin Zhou , Qianbin Wang , Aboozar Monavarfeshani , Kun Gao , Weiqian Jiang , Riki Kawaguchi , Qing Wang , Mingjun Tang , Ryan Donahue , Huyan Meng , Yu Zhang , Anne Jacobi , Wenjun Yan , Jiani Yin , Xinyi Cai , Zhiyun Yang , Shane Hegarty , Joa
Purpose : Regulatory programs governing neuronal death and regenerative failure in neurodegenerative diseases remain poorly understood . In adult mice , optic nerve crush ( ONC ) injury by severing retinal ganglion cell ( RGCs ) axons , results in massive RGC death and regenerative failure . We aim to dissect the transcirptional programs that regulate RGC survival and axon regeneration in nonbiased approaches .
Methods : In this study , we conducted multiple orthogonal , but complementary , functional genomic analyses , starting with a comprehensive , in vivo CRISPR screen of all known mammalian TFs . In parallel , we performed a RNA-seq coupled to an ATAC-seq analysis to define transcriptional networks and their drivers in intact and injured RGCs . Remarkably these different approaches converged on an overlapping set of TFs as critical regulators of neuronal injury responses , highlighting a core transcription program that mediates injury-induced neuronal degenerative outcomes .
Results : Through two orthogonal genome-wide strategies , in vivo CRISPR screening and combined assays of chromatin accessibility ( ATAC-seq ) and gene expression ( RNA-seq ), we identified several TFs that play key roles in injury-induced neuronal loss . We then focused on a set of four TFs – ATF3 , ATF4 , C / EBPγ and CHOP identified through these independent approaches . We showed that their activation and complementary action play key roles in the early engagement of different degeneration-regulatory pathways in injured RGCs . Manipulation of these TFs also led to significant neuroprotection in a newly modified glaucoma model .
Conclusions : Our results reveal core transcription programs that transform an initial axonal insult into a degenerative process and suggest novel strategies for treating neurodegenerative diseases .