Genome-wide interaction target profiling reveals a novel -eRNA activation pathway to control stem cell pluripotency.

Long non-coding RNAs (lncRNAs) constitute an important component of the regulatory apparatus that controls stem cell pluripotency. However, the specific mechanisms utilized by these lncRNAs in the control of pluripotency are not fully characterized. We utilized a RNA reverse transcription-associated trap sequencing (RAT-seq) approach to profile the mouse genome-wide interaction targets for lncRNAs that are screened by RNA-seq. We identified ( enhancer binding lncRNA 20) as a novel lncRNA that is associated with stem cell reprogramming. was differentially transcribed in fibroblasts compared to induced pluripotent stem cells (iPSCs). Notably, we found that utilized a mechanism to interact with the regulatory elements of multiple stemness genes. Using gain- and loss-of-function experiments, we showed that knockdown of caused iPSCs to exit from pluripotency, while overexpression of activated endogenous expression. We further showed that promoted pluripotent reprogramming. Mechanistically, we demonstrated that activated endogenous by binding to the enhancer in , recruiting TET2 demethylase and activating the enhancer-transcribed RNAs. Our data reveal a novel epigenetic mechanism by which a lncRNA controls the fate of stem cells by -regulating the enhancer RNA pathway. We demonstrate the potential for leveraging lncRNA biology to enhance the generation of stem cells for regenerative medicine.