Our body contains multiple cell types that acquire distinct shapes and functions by expressing carefully selected sets of genes. Gene expression begins from transcription of DNA into RNA precursors (pre-mRNAs), which are subsequently processed to produce RNA templates for protein synthesis. Pre-mRNA processing usually involve the addition of a cap structure to the beginning of a transcript, removal of non-coding sequences called introns, and the addition of a poly(A) tail to the transcript end by specialized cleavage/polyadenylation factors.
Pluripotent stem cells are developmentally early progenitors that can self-renew and undergo differentiation, giving rise to all types of cells found in an adult organism. These unique properties of pluripotent stem cells are known to depend on transcriptional activation and repression of different groups of genes. However, regulation of pre-mRNA processing in this system remains largely unexplored.
A paper just published in Nature Communications by researchers from the Centre for Developmental Neurobiology, Yaroslav Kainov and Eugene Makeyev, describes a new pre-mRNA processing mechanism helping pluripotent stem cells to maintain their identity. It turns out that these cells express large amounts of the evolutionarily conserved protein Srrt (also known as Ars2), which prevents premature termination of hundreds of transcripts at unusual cleavage/polyadenylation sites in cap-adjacent intronic sequences. Srrt interacts with the nuclear cap-binding protein complex and facilitates recruitment of an RNA-protein complex called U1, which in turns appears to protect nascent transcripts from unscheduled cleavage/polyadenylation. Importantly, reduced expression of Srrt is sufficient to induce partial differentiation of pluripotent stem cells.
The authors’ work improves our understanding of fundamental mechanisms orchestrating cell type-specific gene expression and suggests new ways to advance stem cell-based technologies for research and therapeutic applications.
By Yaroslav Kainov and Eugene Makeyev