Abstract
BackgroundAtrial fibrillation is a cardiac disease driven by numerous idiopathic etiologies. NUP155 is a nuclear pore complex protein that has been identified as a clinical driver of atrial fibrillation, yet the precise mechanism is unknown. The present study employs a systems biology algorithm to identify effects of NUP155 disruption on cardiogenicity in a model of stem cell-derived differentiation.MethodsEmbryonic stem (ES) cell lines (n = 5) with truncated NUP155 were cultured in parallel with wild type (WT) ES cells (n = 5), and then harvested for RNAseq. Samples were run on an Illumina HiSeq 2000. Reads were analyzed using Strand NGS, Cytoscape, DAVID and Ingenuity Pathways Analysis to deconvolute the NUP155-disrupted transcriptome. Network topological analysis identified key features that controlled framework architecture and functional enrichment.ResultsIn NUP155 truncated ES cells, significant expression changes were detected in 326 genes compared to WT. These genes segregated into clusters that enriched for specific gene ontologies. Deconvolution of the collective framework into discrete sub-networks identified a module with the highest score that enriched for Cardiovascular System Development, and revealed NTRK1/TRKA and SRSF2/SC35 as critical hubs within this cardiogenic module.ConclusionsThe strategy of pluripotent transcriptome deconvolution used in the current study identified a novel association of NUP155 with potential drivers of arrhythmogenic AF. Here, NUP155 regulates cardioplasticity of a sub-network embedded within a larger framework of genome integrity, and exemplifies how transcriptome cardiogenicity in an embryonic stem cell genome is recalibrated by nucleoporin dysfunction.
Highlights
Atrial fibrillation is a cardiac disease driven by numerous idiopathic etiologies
This work is the first to characterize pluripotent transcriptome remodeling regulated by NUP155, where we identify novel and high value NUP155-regulated candidates associated with atrial fibrillation (AF) etiology
Exome Aggregation Consortium (ExAC) browser revealed that only Nup155 and Nup153 possessed negative missense constraint Z-scores with probability of loss of function (LoF) intolerance metrics of > 0.9, which infers extreme LoF intolerant genes, while the remaining three Nuclear pore complex (NPC) proteins (Nup85, Rae1, and Translocated promoter region (Tpr)) had a positive Z-score with high pLI (Fig. 1b)
Summary
Atrial fibrillation is a cardiac disease driven by numerous idiopathic etiologies. NUP155 is a nuclear pore complex protein that has been identified as a clinical driver of atrial fibrillation, yet the precise mechanism is unknown. Preston et al BMC Systems Biology (2018) 12:62 individuals are diagnosed with idiopathic or lone AF, an unexplained arrhythmia where clinical studies report inconclusive or negative results [5]. Studies to address this gap in knowledge have focused on ion channel gene variants, recent work has attributed significant contributions of several non-ion channel substrates to AF [6,7,8]. Recent studies in eukaryotes have revealed that apart from their canonical function as architectural components of the pore and nucleocytoplasmic transport mediators, nups play a significant role in regulation of transcriptional activity and chromatin structure/ organization that impacts phenotype [13,14,15]. Nup-driven differentiation is conserved among a variety of metazoans, where nups play active roles in development [16,17,18]
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