Zinc Finger RNA-Binding Protein Zn72D Regulates ADAR-Mediated RNA Editing in Neurons

Abstract

Highlights d Drosophila Zn72D is a broadly influential regulator of neuronal A-to-I RNA editing d Zn72D regulates ADAR protein levels and editing levels at hundreds of editing sites d Loss of Zn72D causes morphological defects at the neuromuscular junction d Zn72D regulation of editing is conserved in mammalian neurons

Unbiased Identification of trans Regulators of ADAR and A-to-I RNA Editing

“…It will be interesting to more thoroughly explore the role of all DZF-domain-containing proteins, in interacting with ADARs and regulating editing. In concurrent work (Sapiro et al, 2020), we show that the fly homolog of ZFR, Zinc-finger protein at 72D (Zn72D), regulates over half of editing events in the fly brain, and that knockdown of ZFR leads to a decrease in a large number of editing events in mouse primary neurons. Zn72D also interacts with Drosophila ADAR (dADAR) in an RNA-dependent manner, suggesting a similar mechanism to ILF3 regulation of ADARs that we detail here, but ZFR appears to be a positive regulator of editing, in contrast with ILF3.…”

Parallel evolution of a splicing program controlling neuronal excitability in flies and mammals

“…P-values from Mann-Whitney U tests. F. Cross-regulation of eMIC-dependent exons by other RNA binding proteins (RBPs) in fly brains, data from 62 . In red/blue, number of exons regulated in the same/opposite direction between each RBP and the eMIC domain at two ΔPSI levels.…”

“…In contrast, analysis of a recent dataset from first-instar larval (L1) CNS where two members of the ELAV family were knocked out 62 gave very different results. embryonic lethal abnormal vision (Elav) is an RBP widely used as a neuronal marker that, among other functions, can regulate neuronal AS and APA, and have redundant roles with its paralog found in neurons (Fne) 63 .…”

“…To test the overlap with other splicing programs controlled by different RBPs we used a publicly available dataset on RBP KDs in the fly brain ( 62 , Table S2). We calculated the ΔPSI between each RBP KD and the control GFP-KD sample for all eMIC-dependent exons and considered as regulated those with an |ΔPSI| ≥ 20 or 25.…”

“…RBPs often cross-regulate each other and co-regulate the splicing of individual AS exons 41,[47][48][49] . Hence, we searched for trans-acting factors whose regulatory programs may overlap with eMIC-dependent splicing by analysing a recent dataset on RBP knockdowns on fly brains 45 (Figure 5F and Supp. Figure 7D).…”