RNA Degradation in Pluripotent Stem Cells: Mechanisms, Crosstalk, and Fate Regulation

Pluripotent stem cells (PSCs) exhibit remarkable self-renewal capacity and differentiation potential, necessitating tight regulation of gene expression at both transcriptional and post-transcriptional levels. Among post-transcriptional mechanisms, RNA turnover and degradation together play pivotal roles in maintaining transcriptome homeostasis and controlling RNA stability. RNA degradation plays a pivotal role in determining transcript stability for both messenger RNAs (mRNAs) and non-coding RNAs (ncRNAs), thereby influencing cell identity and fate transitions. The core RNA decay machinery, which includes exonucleases, decapping complexes, RNA helicases, and the RNA exosome, ensures timely and selective decay of transcripts. In addition, RNA modifications such as 5' capping and N6-methyladenosine (m⁶A) further modulate RNA stability, contributing to the fine-tuning of gene regulatory networks essential for maintaining PSC states. Recent single-cell and multi-omics studies have revealed that RNA degradation exhibits heterogeneous and dynamic kinetics during cell fate transitions, highlighting its role in preserving transcriptome homeostasis. Conversely, disruption of RNA decay pathways has been implicated in developmental defects and disease, underscoring their potential as therapeutic targets. Collectively, RNA degradation emerges as a central regulator of PSC biology, integrating the decay of both mRNAs and ncRNAs to orchestrate pluripotency maintenance, lineage commitment, and disease susceptibility.