Abstract MP145: Potential Functions of the Nuclear Basket Associated With Dilated Cardiomyopathy

Abstract

Objectives: NUP153 overexpression is clinically correlated with cardiomyopathies, specifically dilated cardiomyopathy (DCM). In combination with the nuclear pore complex (NPC) proteins TPR and NUP50, all three form the basket structure of the NPC that sits within the nuclear envelope. The nuclear basket regulates chromatin dynamics and nuclear export, yet its potential role in cardiopathological development and progression remains unknown. This study was thus carried out to elucidate possible functional roles for nuclear basket nucleoporins in cardiac biology. Methods: Human induced pluripotent stem cells (hiPSCs) with endogenous mEGFP tagged NUP153 were differentiated into cardiomyocytes (hiPSC-CMs) via direct differentiation. Beating started ~ Day 10 and contractile areas were analyzed for contraction velocity and magnitude. NUP153 mobility in hiPSCs and hiPSC-CMs was determined by iFRAP experiments. Bioinformatic analysis of a clinical dilated cardiomyopathy dataset (GSE29819) returned a focused ‘nuclear envelope’ gene list that was uploaded to Ingenuity Pathways Analysis for network analysis. Results: Within hiPSC-CM beating foci (A), NUP153 mobility decreased and went from a biphasic to a monophasic decay curve (B). Bioinformatic analysis of a DCM dataset (C) revealed expression changes in TPR and NUP50 , with no significant changes in NUP153 (D). Conclusions: A switch to monophasic decay kinetics of NUP153 in hiPSC-CMs suggests prioritization of stable slow pools that may reflect changes in global transcriptome regulation. In DCM, differential nucleoporin gene expression changes implicate discrete functional disruptions within the nuclear basket.