Silnr1 promotes pluripotent induction by coordinating Cohesin SMC1-mediated nuclear remodeling

Epigenetic reprogramming of somatic cells into pluripotent cells provides a versatile and ethical methodology to create patient-specific pluripotent stem cells (iPSCs) for use in regenerative medicine. The Cohesin complex is a vital component that is needed to maintain the 3-dimensional structure of the genome. The formation of transcriptional activation chromatin loops represents a critical epigenetic step on the road to pluripotent reprogramming. To explore the Cohesin chromatin architecture, we performed RNA immunoprecipitation sequencing to profile the long noncoding RNAs (lncRNAs) that interact with Cohesin SMC1 differentially during reprogramming. We identified Silnr1 as a novel reprogramming-associated lncRNA, which is not only a critical component of the Cohesin SMC1 complex, but is also specifically activated during the induction of pluripotency. Silnr1 knockdown triggered stem cells to exit from pluripotency, while induced overexpression of this lncRNA promoted pluripotent reprogramming of fibroblasts. Using RNA reverse transcription-associated trap sequencing (RAT-seq) to profile the genome-wide binding target interaction network, we demonstrated that Silnr1 bound to both the Oct4 (Pou5f1) promoter and enhancer, where it recruited SMC1 and orchestrated a functional intrachromosomal loop that is needed for the establishment of induced pluripotency. These data reveal a previously uncharacterized regulatory pathway, in which lncRNA Silnr1 acts as a chromatin factor to help overcome epigenetic bottlenecks on the path to stem cell reprogramming.