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Exit from Pluripotency Is Gated by Intracellular Redistribution of the bHLH Transcription Factor Tfe3

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 p...

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Autores principales: Betschinger, Joerg, Nichols, Jennifer, Dietmann, Sabine, Corrin, Philip D., Paddison, Patrick J., Smith, Austin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cell Press 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3661979/
https://www.ncbi.nlm.nih.gov/pubmed/23582324
http://dx.doi.org/10.1016/j.cell.2013.03.012
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author Betschinger, Joerg
Nichols, Jennifer
Dietmann, Sabine
Corrin, Philip D.
Paddison, Patrick J.
Smith, Austin
author_facet Betschinger, Joerg
Nichols, Jennifer
Dietmann, Sabine
Corrin, Philip D.
Paddison, Patrick J.
Smith, Austin
author_sort Betschinger, Joerg
collection PubMed
description 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.
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spelling pubmed-36619792013-05-23 Exit from Pluripotency Is Gated by Intracellular Redistribution of the bHLH Transcription Factor Tfe3 Betschinger, Joerg Nichols, Jennifer Dietmann, Sabine Corrin, Philip D. Paddison, Patrick J. Smith, Austin Cell Article 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. Cell Press 2013-04-11 /pmc/articles/PMC3661979/ /pubmed/23582324 http://dx.doi.org/10.1016/j.cell.2013.03.012 Text en © 2013 ELL & Excerpta Medica. https://creativecommons.org/licenses/by/3.0/ Open Access under CC BY 3.0 (https://creativecommons.org/licenses/by/3.0/) license
spellingShingle Article
Betschinger, Joerg
Nichols, Jennifer
Dietmann, Sabine
Corrin, Philip D.
Paddison, Patrick J.
Smith, Austin
Exit from Pluripotency Is Gated by Intracellular Redistribution of the bHLH Transcription Factor Tfe3
title Exit from Pluripotency Is Gated by Intracellular Redistribution of the bHLH Transcription Factor Tfe3
title_full Exit from Pluripotency Is Gated by Intracellular Redistribution of the bHLH Transcription Factor Tfe3
title_fullStr Exit from Pluripotency Is Gated by Intracellular Redistribution of the bHLH Transcription Factor Tfe3
title_full_unstemmed Exit from Pluripotency Is Gated by Intracellular Redistribution of the bHLH Transcription Factor Tfe3
title_short Exit from Pluripotency Is Gated by Intracellular Redistribution of the bHLH Transcription Factor Tfe3
title_sort exit from pluripotency is gated by intracellular redistribution of the bhlh transcription factor tfe3
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3661979/
https://www.ncbi.nlm.nih.gov/pubmed/23582324
http://dx.doi.org/10.1016/j.cell.2013.03.012
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