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

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. Hawkins, R. T. Moon, C. B. Ware, P. J. Paddison, H. Ruohola-Baker

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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.

Original languageEnglish
Article number632
Pages (from-to)632
JournalNature Communications
Volume10
Issue number1
DOIs
Publication statusPublished - 7 Feb 2019

Keywords

  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/genetics
  • CRISPR-Cas Systems/genetics
  • Cell Line
  • Estrone/genetics
  • Humans
  • Immunoprecipitation
  • Mechanistic Target of Rapamycin Complex 1/genetics
  • Mechanistic Target of Rapamycin Complex 2/genetics
  • Proteomics
  • Receptors, Estrogen/genetics
  • Wnt Signaling Pathway/genetics

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    Mathieu, J., Detraux, D., Kuppers, D., Wang, Y., Cavanaugh, C., Sidhu, S., Levy, S., Robitaille, A. M., Ferreccio, A., Bottorff, T., McAlister, A., Somasundaram, L., Artoni, F., Battle, S., Hawkins, R. D., Moon, R. T., Ware, C. B., Paddison, P. J., & Ruohola-Baker, H. (2019). Folliculin regulates mTORC1/2 and WNT pathways in early human pluripotency. Nature Communications, 10(1), 632. [632]. https://doi.org/10.1038/s41467-018-08020-0