Exit from Pluripotency is Gated by Intracellular Redistribution of the BHLH Transcription Factor Tfe3

Overview

Journal Cell

Publisher Cell Press

Specialty Cell Biology

Date 2013 Apr 16

PMID 23582324

Citations 188

Authors

Joerg Betschinger

Jennifer Nichols

Sabine Dietmann

Philip D Corrin

Patrick J Paddison

Austin Smith

Affiliations

Soon will be listed here.

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.

Citing Articles

Parallel genome-scale CRISPR-Cas9 screens uncouple human pluripotent stem cell identity versus fitness.

Rosen B, Li Q, Cho H, Liu D, Yang D, Graff S Nat Commun. 2024; 15(1):8966.

PMID: 39419994 PMC: 11487130. DOI: 10.1038/s41467-024-53284-4.

FoxO transcription factors actuate the formative pluripotency specific gene expression programme.

Santini L, Kowald S, Cerron-Alvan L, Huth M, Fabing A, Sestini G Nat Commun. 2024; 15(1):7879.

PMID: 39251582 PMC: 11384738. DOI: 10.1038/s41467-024-51794-9.

Advances in Molecular Mechanisms of Kidney Disease: Integrating Renal Tumorigenesis of Hereditary Cancer Syndrome.

Cicchetti R, Basconi M, Litterio G, Mascitti M, Tamborino F, Orsini A Int J Mol Sci. 2024; 25(16).

PMID: 39201746 PMC: 11355026. DOI: 10.3390/ijms25169060.

Propagating pluripotency - The conundrum of self-renewal.

Smith A Bioessays. 2024; 46(12):e2400108.

PMID: 39180242 PMC: 11589686. DOI: 10.1002/bies.202400108.

PUFFFIN: an ultra-bright, customisable, single-plasmid system for labelling cell neighbourhoods.

Lebek T, Malaguti M, Boezio G, Zoupi L, Briscoe J, Elfick A EMBO J. 2024; 43(18):4110-4135.

PMID: 38997504 PMC: 11405414. DOI: 10.1038/s44318-024-00154-w.

References

Laplante M, Sabatini D . mTOR signaling in growth control and disease. Cell. 2012; 149(2):274-93. PMC: 3331679. DOI: 10.1016/j.cell.2012.03.017. View

Martello G, Sugimoto T, Diamanti E, Joshi A, Hannah R, Ohtsuka S . Esrrb is a pivotal target of the Gsk3/Tcf3 axis regulating embryonic stem cell self-renewal. Cell Stem Cell. 2012; 11(4):491-504. PMC: 3465555. DOI: 10.1016/j.stem.2012.06.008. View

Nichols J, Smith A . Naive and primed pluripotent states. Cell Stem Cell. 2009; 4(6):487-92. DOI: 10.1016/j.stem.2009.05.015. View

Baba M, Keller J, Sun H, Resch W, Kuchen S, Suh H . The folliculin-FNIP1 pathway deleted in human Birt-Hogg-Dubé syndrome is required for murine B-cell development. Blood. 2012; 120(6):1254-61. PMC: 3418720. DOI: 10.1182/blood-2012-02-410407. View

Wray J, Kalkan T, Smith A . The ground state of pluripotency. Biochem Soc Trans. 2010; 38(4):1027-32. DOI: 10.1042/BST0381027. View

Miller A, Du J, Rowan S, Hershey C, Widlund H, Fisher D . Transcriptional regulation of the melanoma prognostic marker melastatin (TRPM1) by MITF in melanocytes and melanoma. Cancer Res. 2004; 64(2):509-16. DOI: 10.1158/0008-5472.can-03-2440. View

Ying Q, Wray J, Nichols J, Batlle-Morera L, Doble B, Woodgett J . The ground state of embryonic stem cell self-renewal. Nature. 2008; 453(7194):519-23. PMC: 5328678. DOI: 10.1038/nature06968. View

Yang S, Kalkan T, Morrisroe C, Smith A, Sharrocks A . A genome-wide RNAi screen reveals MAP kinase phosphatases as key ERK pathway regulators during embryonic stem cell differentiation. PLoS Genet. 2012; 8(12):e1003112. PMC: 3521700. DOI: 10.1371/journal.pgen.1003112. View

Kunath T, Saba-El-Leil M, Almousailleakh M, Wray J, Meloche S, Smith A . FGF stimulation of the Erk1/2 signalling cascade triggers transition of pluripotent embryonic stem cells from self-renewal to lineage commitment. Development. 2007; 134(16):2895-902. DOI: 10.1242/dev.02880. View

10.

Brannon M, Brown J, Bates R, Kimelman D, Moon R . XCtBP is a XTcf-3 co-repressor with roles throughout Xenopus development. Development. 1999; 126(14):3159-70. DOI: 10.1242/dev.126.14.3159. View

11.

Chanut-Delalande H, Jung A, Baer M, Lin L, Payre F, Affolter M . The Hrs/Stam complex acts as a positive and negative regulator of RTK signaling during Drosophila development. PLoS One. 2010; 5(4):e10245. PMC: 2858154. DOI: 10.1371/journal.pone.0010245. View

12.

Doble B, Patel S, Wood G, Kockeritz L, Woodgett J . Functional redundancy of GSK-3alpha and GSK-3beta in Wnt/beta-catenin signaling shown by using an allelic series of embryonic stem cell lines. Dev Cell. 2007; 12(6):957-71. PMC: 4485918. DOI: 10.1016/j.devcel.2007.04.001. View

13.

Guo G, Yang J, Nichols J, Hall J, Eyres I, Mansfield W . Klf4 reverts developmentally programmed restriction of ground state pluripotency. Development. 2009; 136(7):1063-9. PMC: 2685927. DOI: 10.1242/dev.030957. View

14.

Kaji K, Caballero I, MacLeod R, Nichols J, Wilson V, Hendrich B . The NuRD component Mbd3 is required for pluripotency of embryonic stem cells. Nat Cell Biol. 2006; 8(3):285-92. DOI: 10.1038/ncb1372. View

15.

Piao X, Kobayashi T, Wang L, Shiono M, Takagi Y, Sun G . Regulation of folliculin (the BHD gene product) phosphorylation by Tsc2-mTOR pathway. Biochem Biophys Res Commun. 2009; 389(1):16-21. DOI: 10.1016/j.bbrc.2009.08.070. View

16.

Ivanova N, Dobrin R, Lu R, Kotenko I, Levorse J, DeCoste C . Dissecting self-renewal in stem cells with RNA interference. Nature. 2006; 442(7102):533-8. DOI: 10.1038/nature04915. View

17.

Hasumi H, Baba M, Hong S, Hasumi Y, Huang Y, Yao M . Identification and characterization of a novel folliculin-interacting protein FNIP2. Gene. 2008; 415(1-2):60-7. PMC: 2727720. DOI: 10.1016/j.gene.2008.02.022. View

18.

Hong S, Oh H, Valera V, Baba M, Schmidt L, Linehan W . Inactivation of the FLCN tumor suppressor gene induces TFE3 transcriptional activity by increasing its nuclear localization. PLoS One. 2011; 5(12):e15793. PMC: 3012117. DOI: 10.1371/journal.pone.0015793. View

19.

Tarleton H, Lemischka I . Delayed differentiation in embryonic stem cells and mesodermal progenitors in the absence of CtBP2. Mech Dev. 2009; 127(1-2):107-19. PMC: 2818266. DOI: 10.1016/j.mod.2009.10.002. View

20.

Kobayashi T, Minowa O, KUNO J, Mitani H, Hino O, Noda T . Renal carcinogenesis, hepatic hemangiomatosis, and embryonic lethality caused by a germ-line Tsc2 mutation in mice. Cancer Res. 1999; 59(6):1206-11. View