NUP155 insufficiency recalibrates a pluripotent transcriptome with network remodeling of a cardiogenic signaling module

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.Electronic supplementary materialThe online version of this article (10.1186/s12918-018-0590-x) contains supplementary material, which is available to authorized users.

Gene set enrichment analysis and meta-analysis to identify six key genes regulating and controlling the prognosis of esophageal squamous cell carcinoma

“…NUP155 is specific in many tissues, but its specificity in esophageal cancer tissues has not been tested. As a nuclear pore complex protein, NUP155 has been identified as a clinical driver of atrial fibrillation (37,38) and NUP155 may be a new potential drug to target NUP214-ABL1-positive T-cell acute lymphoblastic leukemia (39). Some studies have explored the role that the three genes play on RNA transport pathways; however, little of this research explains the relationship between these genes and cancer, let alone their relationship with ESCC.…”

Emerging roles for nucleoporins in reproductive cellular physiology

“…Next generation sequencing accelerates current understanding of global molecular dynamics underlying development (Faustino et al 2008; Preston et al 2018), and has emerged as an invaluable and versatile tool with the ability to identify rare genetic changes (Smith et al 2007). Application of this technology is valuable for basic and clinical research and provides unique insights into system wide epigenomic and (or) transcriptome remodeling that occurs under normal and diseased conditions (Ernst et al 2017; Wyles et al 2015; Zhang et al 2017).…”

“…Individual nucleoporins have demonstrated gene regulation of pluripotency independent of their canonical role in architectural support and facilitated transport functions of the NPC (Gomez-Cavazos and Hetzer 2015). For example, analysis of an embryonic stem (ES) cell line deficient in the NPC inner ring subcomplex nucleoporin, Nup155, revealed global dysregulation of gene expression in Nup155 compromised ES cells (Preston et al 2018). Abnormal gene over- and under-expression in the Nup155 -insufficient ES cell line led to reprioritized functional gene ontologies that included membrane biology and RNA metabolism.…”

“…Abnormal gene over- and under-expression in the Nup155 -insufficient ES cell line led to reprioritized functional gene ontologies that included membrane biology and RNA metabolism. Furthermore, the splicing factor Srsf2 was identified as essential to the overall architecture of a cardiogenic gene subnetwork (Preston et al 2018). Previous work in which conditional knockout of Srsf2 in ventricular tissue leads to poor calcium handling upon increased pacing has been reported (Ding et al 2004), in line with the effects observed on contractile embryoid bodies derived from Nup155 -deficient ES cells (Preston et al 2018).…”

“…Furthermore, the splicing factor Srsf2 was identified as essential to the overall architecture of a cardiogenic gene subnetwork (Preston et al 2018). Previous work in which conditional knockout of Srsf2 in ventricular tissue leads to poor calcium handling upon increased pacing has been reported (Ding et al 2004), in line with the effects observed on contractile embryoid bodies derived from Nup155 -deficient ES cells (Preston et al 2018). This is supported by earlier observations of a clinical mutation for NUP155 associated with incidences of sudden cardiac death in a consanguineous pediatric cohort (Zhang et al 2008).…”