title: Exit from pluripotency is gated by intracellular redistribution of the bHLH transcription factor Tfe3.
abstract: Factors that sustain self-renewal of mouse embryonic stem cells (ESCs) are well described. In contrast, the machinery regulating exit from pluripotency is ill defined. In a large-scale small interfering RNA (siRNA) screen, we found that knockdown of the tumor suppressors Folliculin (Flcn) and Tsc2 prevent ESC commitment. Tsc2 lies upstream of mammalian target of rapamycin (mTOR), whereas Flcn acts downstream and in parallel. Flcn with its interaction partners Fnip1 and Fnip2 drives differentiation by restricting nuclear localization and activity of the bHLH transcription factor Tfe3. Conversely, enforced nuclear Tfe3 enables ESCs to withstand differentiation conditions. Genome-wide location and functional analyses showed that Tfe3 directly integrates into the pluripotency circuitry through transcriptional regulation of Esrrb. These findings identify a cell-intrinsic rheostat for destabilizing ground-state pluripotency to allow lineage commitment. Congruently, stage-specific subcellular relocalization of Tfe3 suggests that Flcn-Fnip1/2 contributes to developmental progression of the pluripotent epiblast in vivo.
authors.affiliation: Wellcome Trust-Medical Research Council Stem Cell Institute, University of Cambridge, Cambridge CB2 1QR, UK. jb579@cam.ac.uk
authors.forename: Joerg
authors.initials: J
authors.lastname: Betschinger
authors.forename: Jennifer
authors.initials: J
authors.lastname: Nichols
authors.forename: Sabine
authors.initials: S
authors.lastname: Dietmann
authors.forename: Philip D
authors.initials: PD
authors.lastname: Corrin
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Paddison
authors.forename: Austin
authors.initials: A
authors.lastname: Smith
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism; D002454:Cell Differentiation; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism; D004970:Estrone / Q000235:genetics / Q000378:metabolism; D053263:Gene Regulatory Networks; D051379:Mice; D008810:Mice, Inbred C57BL; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D002352:Carrier Proteins; C581709:FNIP1 protein, mouse; C574800:MAPO1 protein, mouse; C068486:Tcfe3 protein, mouse; D004970:Estrone; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases