LncRNAs coordinate doxycycline-induced gene expression response in human iPSCs (ATAC-seq)

Long non-coding RNAs are known to regulate gene expression. However, less is understood about the temporal dynamics of lncRNA regulation, particularly how they influence early, middle, and late gene expression. To investigate this, we generated 17 genetically defined, Doxycycline-inducible lncRNA transgene hiPSC lines and performed high-density time-course RNA-seq and ATAC-seq. We observed that most lncRNA transgenes showed expected induction and subsequent changes in gene expression. However, the putative target genes of the different lncRNAs had substantial overlap, and control cell lines showed a similar set of induced genes, leading us to conclude that the substantial effect of doxycycline prevented identification of lncRNA-specific effects. Although doxycycline-induced gene expression changes have been reported previously, the large size of the current study allowed us to identify a highly reproducible doxycycline response gene signature (DRGS). We further observe that the DRGS occurs in most human cell lines tested with Dox exposure. Notably, the DRGS includes 18 endogenous lncRNAs that exhibit highly reproducible temporal regulation by Dox itself. Our results suggest these lncRNAs act synergistically as "co-response amplifiers" associated with the stress response; some are linked to different cell fates, such as epithelial-mesenchymal transition or nervous system development.