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. Alternative polyadenylation exerts post-transcriptional control over cell fate decisions and pluripotency.
Bibliographical noteFunding Information:
We thank Maris Handley, Amy Galvin, Marianne Gesner, and Eric Surette of the Harvard Stem Cell Institute flow cytometry core. We are grateful to David Sykes for sharing HOXB8-ER/LYZ-GFP cells. We thank Aaron Goldstrohm and members of the Hochedlinger lab for discussions. K.H. was supported by funds from the MGH , NIH ( R01 HD058013-06 , P01GM099134-06 ), and the Gerald and Darlene Jordan Chair in Regenerative Medicine . J.B. is grateful for support from the NIH ( 1F32HD078029-01A1 ). B.D.S. was supported by an EMBO long-term fellowship ( ALTF 1143-2015 ). Y.S. was supported by NIH grants GM090056 and CA17488 . G.H. was supported by the NIH Intramural Research Program ( Z01ES102745 ). S.J.E. was supported by the NIH ( AG11085 ).
- Alternative polyadenylation
- embryonic stem cells
- epigenetic regulation
- induced pluripotent stem cells
- induced trophoblast stem cells