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GATA3 induces human T-cell commitment by restraining Notch activity and repressing NK-cell fate

Van de Walle, Inge and Dolens, Anne-Catherine and Durinck, Kaat and De Mulder, Katrien and Van Loocke, Wouter and Damle, Sagar and Waegemans, Els and De Medts, Jelle and Velghe, Imke and De Smedt, Magda and Vandekerckhove, Bart and Kerre, Tessa and Plum, Jean and Leclercq, Georges and Rothenberg, Ellen V. and Van Vlierberghe, Pieter and Speleman, Frank and Taghon, Tom (2016) GATA3 induces human T-cell commitment by restraining Notch activity and repressing NK-cell fate. Nature Communications, 7 . Art. No. 11171. ISSN 2041-1723. PMCID PMC4823830.

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The gradual reprogramming of haematopoietic precursors into the T-cell fate is characterized by at least two sequential developmental stages. Following Notch1-dependent T-cell lineage specification during which the first T-cell lineage genes are expressed and myeloid and dendritic cell potential is lost, T-cell specific transcription factors subsequently induce T-cell commitment by repressing residual natural killer (NK)-cell potential. How these processes are regulated in human is poorly understood, especially since efficient T-cell lineage commitment requires a reduction in Notch signalling activity following T-cell specification. Here, we show that GATA3, in contrast to TCF1, controls human T-cell lineage commitment through direct regulation of three distinct processes: repression of NK-cell fate, upregulation of T-cell lineage genes to promote further differentiation and restraint of Notch activity. Repression of the Notch1 target gene DTX1 hereby is essential to prevent NK-cell differentiation. Thus, GATA3-mediated positive and negative feedback mechanisms control human T-cell lineage commitment.

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Rothenberg, Ellen V.0000-0002-3901-347X
Additional Information:© 2016 Macmillan Publishers Limited. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit Received 11 August 2015; Accepted 25 February 2016; Published 06 April 2016. We thank I-Cheng Ho (Harvard Medical School) for providing ROG cDNA, Warren Pear (University of Pennsylvania) for the DTX1 construct and TCF12alt primer sequences, Avinash Bhandoola (NIH) for TCF7 construct, Juan-Carlos Zuniga-Pflucker (University of Toronto) for OP9 stromal cells, Marissa Morales Del Real and Jingli Zhang (California Institute of Technology) for help with ChIP-Seq experiments and Igor Antoshechkin and colleagues (California Institute of Technology) for library preparation and sequencing of ChIP DNA. This work was supported by the Odysseus programme of the Fund for Scientific Research Flanders (FWO) and grants from the FWO, the Flemish Institute for the advancement of Scientific-Technological Research in the Industry (IWT), the Concerted Research Action of Ghent University (GOA) and the Interuniversity Attraction Poles Program (IUAP) from the Belgian Science Policy. IVdW is a postdoctoral researcher of the FWO. TK is a senior clinical researcher of the FWO. All gene expression profiling data has been deposited in the GEO database (GSE71753). Author Contributions: IVdW performed the experiments, analysed the data and wrote the manuscript; ACD, KD, KDM and EW performed the experiments and analysed the data; WVL and SD analysed the data; JDM, IV and MDS performed the experiments; BV, TK and GL provided the reagents; JP, EVR, PVV and FS provided the reagents and intellectual guidance; TT performed the experiments, designed the research, analysed the data and wrote the manuscript. The authors declare no competing financial interests.
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Fonds Wetenschappelijk Onderzoek - Vlaanderen (FWO)UNSPECIFIED
Belgian Science Policy Office (BELSPO)UNSPECIFIED
PubMed Central ID:PMC4823830
Record Number:CaltechAUTHORS:20160429-141209078
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Official Citation:Van de Walle, I. et al. GATA3 induces human T cell commitment by restraining Notch activity and repressing NK-cell fate. Nat. Commun. 7:11171 doi: 10.1038/ncomms11171 (2016).
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:66556
Deposited By: Tony Diaz
Deposited On:02 May 2016 00:10
Last Modified:03 Oct 2019 09:57

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