Nudt21 Controls Cell Fate by Connecting Alternative Polyadenylation to Chromatin Signaling

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

Research output: Contribution to journalArticlepeer-review

38 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)106-120.e21
JournalCell
Volume172
Issue number1-2
DOIs
StatePublished - Jan 11 2018

Bibliographical note

Funding 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 ).

Publisher Copyright:
© 2017 Elsevier Inc.

Keywords

  • Alternative polyadenylation
  • chromatin
  • embryonic stem cells
  • epigenetic regulation
  • induced pluripotent stem cells
  • induced trophoblast stem cells
  • microRNA
  • pluripotency
  • reprogramming
  • transdifferentiation

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