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01 11, 2018;172 (1-2): 106-120.e21.

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
Author Information
  1. Justin Brumbaugh: Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA.
  2. Bruno Di Stefano: Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA.
  3. Xiuye Wang: Department of Microbiology and Molecular Genetics, School of Medicine, University of California, Irvine, Irvine, CA 92697, USA.
  4. Marti Borkent: Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA.
  5. Elmira Forouzmand: Department of Microbiology and Molecular Genetics, School of Medicine, University of California, Irvine, Irvine, CA 92697, USA.
  6. Katie J Clowers: Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
  7. Fei Ji: Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA.
  8. Benjamin A Schwarz: Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA.
  9. Marian Kalocsay: Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
  10. Stephen J Elledge: Howard Hughes Medical Institute, Brigham and Women's Hospital and Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
  11. Yue Chen: Department of Biochemistry, Molecular Biology, and Biophysics, College of Biological Sciences, University of Minnesota, Saint Paul, MN 55018, USA.
  12. Ruslan I Sadreyev: Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA.
  13. Steven P Gygi: Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
  14. Guang Hu: Epigenetics and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
  15. Yongsheng Shi: Department of Microbiology and Molecular Genetics, School of Medicine, University of California, Irvine, Irvine, CA 92697, USA. Electronic address: yongshes@uci.edu.
  16. Konrad Hochedlinger: Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA. Electronic address: khochedlinger@mgh.harvard.edu.
PMID: 29249356 DOI: 10.1016/j.cell.2017.11.023

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.

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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Grants

  1. R01 GM090056/NIGMS NIH HHS
  2. P01 GM099134/NIGMS NIH HHS
  3. R01 AG011085/NIA NIH HHS
  4. R01 GM067945/NIGMS NIH HHS
  5. R01 HD058013/NICHD NIH HHS
  6. R01 CA177651/NCI NIH HHS
  7. F32 HD078029/NICHD NIH HHS

MeSH Term

Animals
Cells, Cultured
Cellular Reprogramming
Chromatin
Chromatin Assembly and Disassembly
Cleavage And Polyadenylation Specificity Factor
Embryonic Stem Cells
HEK293 Cells
Humans
Mice
Polyadenylation
Signal Transduction

Chemicals

Chromatin
Cleavage And Polyadenylation Specificity Factor
Nudt21 protein, mouse
Journal Article Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural Research Support, Non-U.S. Gov't

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