Folliculin Regulates MTORC1/2 and WNT Pathways in Early Human Pluripotency

Overview

Journal Nat Commun

Specialty Biology

Date 2019 Feb 9

PMID 30733432

Citations 30

Authors

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

Affiliations

Soon will be listed here.

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.

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