Selinexor, a CRM1 inhibitor with anti-senescence activity, modulates the non- coding transcriptome of Hutchinson–Gilford progeria syndrome fibroblasts

Abstract Background Hutchinson-Gilford progeria syndrome (HGPS) is characterized by premature and accelerated aging due to progerin expression, a lamin A mutant variant. Progerin disrupts a variety of cellular processes leading to premature cellular senescence. The senescent phenotype of HGPS cells is functionally linked to the altered gene expression mediated by progerin; nonetheless, the contribution of the noncoding transcriptome to this phenomenon remains to be elucidated. Methods The coding and non-coding transcriptome of HGPS fibroblasts was characterized by bioinformatic analysis of RNA sequencing data. Selected long non-coding RNAs (lncRNAs) were validated by reverse transcription-polymerase chain reaction (RT-PCR) assays Results Altered expression profiling of lncRNAs and enriched cellular pathways were found in HGPS fibroblasts compared with WT fibroblasts. Furthermore, the analysis demonstrated that HGPS fibroblasts treated with selinexor, a CRM1-mediated nuclear export inhibitor with antisenescence activity, reversed missregulation of the lncRNA profile. Finally, four differentially expressed lncRNAs (UB2R2-AS1, MSC-AS1, MBNL1-AS1, and H19) that were predicted to regulate mTOR and senesce pathways and respond to selinexor treatment were validated by RT-PCR assays in HGPS fibroblasts, and in a progerin-inducible cell model, under treatment with selinexor or the vehicle. Conclusion The influence of lncRNAs in the transcriptome profile and the enriched cellular pathways of HGPS fibroblasts was established. Interestingly selinexor treatment restores the expression of specific lncRNAs altered by progerin, targeting the aging-associated pathways mTOR and senescence in HGPS fibroblasts. Overall, these results show that the analysis of the noncoding transcriptome can serve to monitor treatment efficacy and support the use of selinexor as anti-senescent compound in HGPS.