A large intergenic non-coding RNA, lincRNA-RoR, modulates the reprogramming of human induced pluripotent stem cells (iPSCs). The study characterizes the transcriptional reorganization of large intergenic non-coding RNAs (lincRNAs) during iPSC derivation and identifies lincRNAs linked to pluripotency. It shows that lincRNA-RoR is a direct target of key pluripotency transcription factors and modulates reprogramming. The research demonstrates that lincRNAs are regulated independently of protein-coding genes and are tightly associated with the pluripotent state. The study also identifies lincRNAs that are enriched in iPSCs compared to embryonic stem cells (ESCs), suggesting their role in reprogramming. The lincRNA-ST8SIA3 was found to be essential for iPSC derivation, as its knockdown significantly reduced iPSC colony formation. Conversely, overexpression of lincRNA-ST8SIA3 enhanced reprogramming efficiency. The study also shows that lincRNA-ST8SIA3 plays a role in promoting survival in iPSCs and ESCs by preventing the activation of cellular stress pathways. The findings highlight the functional importance of lincRNAs in the establishment and maintenance of pluripotency, and suggest that they may interface with chromatin-modifying complexes to regulate the distinct epigenetic architecture in pluripotent cells. The study provides the first functional example of a lincRNA in establishing iPSCs, naming it lincRNA-RoR for Regulator of Reprogramming.A large intergenic non-coding RNA, lincRNA-RoR, modulates the reprogramming of human induced pluripotent stem cells (iPSCs). The study characterizes the transcriptional reorganization of large intergenic non-coding RNAs (lincRNAs) during iPSC derivation and identifies lincRNAs linked to pluripotency. It shows that lincRNA-RoR is a direct target of key pluripotency transcription factors and modulates reprogramming. The research demonstrates that lincRNAs are regulated independently of protein-coding genes and are tightly associated with the pluripotent state. The study also identifies lincRNAs that are enriched in iPSCs compared to embryonic stem cells (ESCs), suggesting their role in reprogramming. The lincRNA-ST8SIA3 was found to be essential for iPSC derivation, as its knockdown significantly reduced iPSC colony formation. Conversely, overexpression of lincRNA-ST8SIA3 enhanced reprogramming efficiency. The study also shows that lincRNA-ST8SIA3 plays a role in promoting survival in iPSCs and ESCs by preventing the activation of cellular stress pathways. The findings highlight the functional importance of lincRNAs in the establishment and maintenance of pluripotency, and suggest that they may interface with chromatin-modifying complexes to regulate the distinct epigenetic architecture in pluripotent cells. The study provides the first functional example of a lincRNA in establishing iPSCs, naming it lincRNA-RoR for Regulator of Reprogramming.