Folliculin regulates mTORC1/2 and WNT pathways in early human pluripotency.
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
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
07 02 2019
07 02 2019
Historique:
received:
22
06
2017
accepted:
05
12
2018
entrez:
9
2
2019
pubmed:
9
2
2019
medline:
9
4
2019
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 30733432
doi: 10.1038/s41467-018-08020-0
pii: 10.1038/s41467-018-08020-0
pmc: PMC6367455
doi:
Substances chimiques
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
0
ESRRB protein, human
0
Receptors, Estrogen
0
TFE3 protein, human
0
Estrone
2DI9HA706A
Mechanistic Target of Rapamycin Complex 1
EC 2.7.11.1
Mechanistic Target of Rapamycin Complex 2
EC 2.7.11.1
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
632Subventions
Organisme : NIGMS NIH HHS
ID : P01 GM081619
Pays : United States
Organisme : NHLBI NIH HHS
ID : U01 HL099997
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM083867
Pays : United States
Organisme : NHLBI NIH HHS
ID : U01 HL099993
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM097372
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK017047
Pays : United States
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