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Published April 6, 2016 | Published + Supplemental Material
Journal Article Open

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

Abstract

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.

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 http://creativecommons.org/licenses/by/4.0/ 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.

Attached Files

Published - ncomms11171.pdf

Supplemental Material - ncomms11171-s1.pdf

Supplemental Material - ncomms11171-s2.xlsx

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Supplemental Material - ncomms11171-s4.xlsx

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Supplemental Material - ncomms11171-s6.xlsx

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Created:
August 20, 2023
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