Long read RNA sequencing reveals a new long non-coding RNA that regulates somatic cell reprogramming and pluripotency

The recent development of long-read RNA sequencing (lrRNAseq) technologies has paved the way to the exploration of RNA isoform diversity and its relevance to better understand the gene regulatory network that sustains cell fate and plasticity. However, drawing conclusions regarding the functionality of these newly identified isoforms is still very scarce. Here, we devised a very efficient system to reprogram cells towards an induced pluripotent cell state and leveraged the strengths of lrRNAseq in order to study the isoform diversity of reprogramming. This strategy enabled us to identify differential isoforms throughout the reprogramming process, with a pressure on novel non-coding isoforms to be regulated. More specifically, we highlight a new long non-coding RNA (lncRNA) whose isoform switch during reprogramming enhances the conversion of cells’ identity towards pluripotency. Conversely, we show that knocking-down this lncRNA in mouse embryonic stem cells hinders the maintenance of a pluripotent state and primes the cells for differentiation. Together, our study provides a comprehensive resource to study full-length isoform regulation and mechanisms at stake during reprogramming, but more importantly it demonstrates the power of lrRNAseq to identify functionally relevant gene isoforms in the context of pluripotency.