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Folliculin regulates mTORC1/2 and WNT pathways in early human pluripotency

Author

Listed:
  • J. Mathieu

    (University of Washington
    University of Washington
    University of Washington)

  • D. Detraux

    (University of Washington
    University of Washington
    Laboratory of Cellular Biochemistry and Biology (URBC), University of Namur)

  • D. Kuppers

    (Fred Hutchinson Cancer Research Center)

  • Y. Wang

    (University of Washington
    University of Washington)

  • C. Cavanaugh

    (University of Washington
    University of Washington)

  • S. Sidhu

    (University of Washington
    University of Washington)

  • S. Levy

    (University of Washington
    University of Washington)

  • A. M. Robitaille

    (University of Washington
    University of Washington)

  • A. Ferreccio

    (University of Washington
    University of Washington)

  • T. Bottorff

    (University of Washington
    University of Washington)

  • A. McAlister

    (University of Washington
    University of Washington)

  • L. Somasundaram

    (University of Washington
    University of Washington)

  • F. Artoni

    (University of Washington
    University of Washington)

  • S. Battle

    (University of Washington
    University of Washington)

  • R. D. Hawkins

    (University of Washington
    University of Washington)

  • R. T. Moon

    (University of Washington
    University of Washington)

  • C. B. Ware

    (University of Washington
    University of Washington)

  • P. J. Paddison

    (University of Washington
    Fred Hutchinson Cancer Research Center)

  • H. Ruohola-Baker

    (University of Washington
    University of Washington)

Abstract

To reveal how cells exit human pluripotency, we designed a CRISPR-Cas9 screen exploiting the metabolic and epigenetic differences between naïve and primed pluripotent cells. We identify the tumor suppressor, Folliculin(FLCN) as a critical gene required for the exit from human pluripotency. Here we show that FLCN Knock-out (KO) hESCs maintain the naïve pluripotent state but cannot exit the state since the critical transcription factor TFE3 remains active in the nucleus. TFE3 targets up-regulated in FLCN KO exit assay are members of Wnt pathway and ESRRB. Treatment of FLCN KO hESC with a Wnt inhibitor, but not ESRRB/FLCN double mutant, rescues the cells, allowing the exit from the naïve state. Using co-immunoprecipitation and mass spectrometry analysis we identify unique FLCN binding partners. The interactions of FLCN with components of the mTOR pathway (mTORC1 and mTORC2) reveal a mechanism of FLCN function during exit from naïve pluripotency.

Suggested Citation

  • J. Mathieu & D. Detraux & D. Kuppers & Y. Wang & C. Cavanaugh & S. Sidhu & S. Levy & A. M. Robitaille & A. Ferreccio & T. Bottorff & A. McAlister & L. Somasundaram & F. Artoni & S. Battle & R. D. Hawk, 2019. "Folliculin regulates mTORC1/2 and WNT pathways in early human pluripotency," Nature Communications, Nature, vol. 10(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-018-08020-0
    DOI: 10.1038/s41467-018-08020-0
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