- Brumbaugh, Justin;
- Di Stefano, Bruno;
- Wang, Xiuye;
- Borkent, Marti;
- Forouzmand, Elmira;
- Clowers, Katie J;
- Ji, Fei;
- Schwarz, Benjamin A;
- Kalocsay, Marian;
- Elledge, Stephen J;
- Chen, Yue;
- Sadreyev, Ruslan I;
- Gygi, Steven P;
- Hu, Guang;
- Shi, Yongsheng;
- Hochedlinger, Konrad
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.