Nudt21 Controls Cell Fate by Connecting Alternative Polyadenylation to Chromatin Signaling

Cell fate transitions involve rapid gene expression changes and global chromatin remodeling, yet the underlying regulatory pathways remain incompletely understood. Here, we identified the RNA-processing factor Nudt21 as a novel regulator of cell fate change using transcription-factor-induced reprogramming as a screening assay. Suppression of Nudt21 enhanced the generation of induced pluripotent stem cells, facilitated transdifferentiation into trophoblast stem cells, and impaired differentiation of myeloid precursors and embryonic stem cells, suggesting a broader role for Nudt21 in cell fate change. We show that Nudt21 directs differential polyadenylation of over 1,500 transcripts in cells acquiring pluripotency, although only a fraction changed protein levels. Remarkably, these proteins were strongly enriched for chromatin regulators, and their suppression neutralized the effect of Nudt21 during reprogramming. Collectively, our data uncover Nudt21 as a novel post-transcriptional regulator of cell fate and establish a direct, previously unappreciated link between alternative polyadenylation and chromatin signaling. [Display omitted] •shRNA screen identifies mRNA processing factor Nudt21 as a regulator of cell fate•Nudt21 knockdown enhances reprogramming but disrupts ESC/myeloid differentiation•Nudt21 suppression induces alternative polyadenylation for hundreds of transcripts•Chromatin regulators are enriched among Nudt21 targets important for reprogramming Alternative polyadenylation exerts post-transcriptional control over cell fate decisions and pluripotency.