Abstract 9365: Psip1a is Critical for Vascular Development in Zebrafish

Abstract

Transcription coactivators function in variety ways which effectively facilitate the process of transcription and play an essential role in gene regulation. Among them, Psip1, the gene codes LEDGF/p75, has been implicated in cell survival, cancer, autoimmune diseases and HIV pathogenesis. Especially for its role in HIV replication, psip1 tethers and targets HIV integrase to the bodies of active genes, which makes it a novel target for anti-HIV treatment. However, the basic biology of psip1 is not fully elucidated, and such antiviral drugs may have unexpected side effect. Here, we show that psip1a is essential for vascular development in zebrafish. Knockdown or knockout of psip1a caused the structure disruption in the caudal vein plexus suggesting the cell death of endothelial cells. Interestingly, RNA-seq data suggested that psip1a is the master regulator for p53 signal pathway. Indeed, our data showed that psip1a directly associates to the alternative p53 promoter and potentially regulates Δ113p53 expression to antagonize p53 pathway and exhibited an anti-apoptotic effect. Such function of psip1a is medicated by IBD domain which is important for recruiting its binding partners for different functions of psip1. Zebrafish embryos treated with non-catalytic integrase inhibitors (NCINIs) showed the same vascular defects as the knockdown of psip1a, which was also mediated by the IBD domain. This unexpectedly side effect suggests a unforeseen risk of using NCINIs in antiviral treatment. Our results demonstrate the importance of psip1 in vascular development and how it regulates the p53 pathway to inhibit apoptosis. We anticipate our study to provide a new insight into the role of psip1 in vascular development. Better understanding the mechanism of psip1 function would also help to prevent unexpectedly side effects of new antiviral drug in HIV treatment.