Abstract 18285: Embryonic Stem Cell Transcriptome Remodeling by a Nucleoporin Substrate for Atrial Fibrillation

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Introduction: Nup155 is a nuclear pore complex protein identified as a potential clinical driver of idiopathic atrial fibrillation (Afib), however its mechanism of action is unknown. Here we examine effects of gene-trapped Nup155 haploinsufficiency (Nup155et) on an embryonic stem (ES) cell transcriptome prior to ES cell differentiation into cardiomyocyte-containing embryoid bodies.

Methods: Nup155et ES cell lines (n=5) were cultured in parallel with wild type (WT) ES cells (n=5), total RNA was harvested for Illumina sequencing and analyzed using Strand NGS. Functional annotation and gene ontology enrichment were executed using DAVID and Ingenuity Pathways Analysis, and gene network analysis was performed using Cytoscape.

Results: Transcriptome profiling of Nup155et and WT ES cells (A) depicted significant changes of 326 genes (176 upregulated and 150 downregulated genes) in the Nup155et group (B). These genes segregated into functional clusters within the up and downregulated sub-transcriptomes that enriched for specific gene ontologies (C-D). Major network drivers included TP53, a regulator of genome integrity. Deconvolution of the collective framework into sub-networks identified a module with the highest significance score that enriched for Cardiovascular System Development and identified TRKA as a primary hub, followed by SRSF2; comparison of RNAseq abundances confirmed magnitude and significance of expression changes for both transcripts (E-F).

Conclusions: Cardiac fate is secured by intricate execution of molecular programs, and the strategy of network deconvolution used here forecasts arrhythmogenic predisposition within a pluripotent genome. Here, NUP155 anchors cardioplasticity of a molecular sub-network embedded within a larger framework driven by genome integrity maintenance, and exemplifies how transcriptome cardiogenicity in an embryonic stem cell genome is recalibrated by nucleoporin dysfunction.

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