title: 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.
authors.affiliation: Faculty of Medicine and Health Sciences, Department of Clinical Chemistry, Microbiology and Immunology, Ghent University, University Hospital Ghent, 4BlokA, De Pintelaan 185, B-9000 Ghent, Belgium.
authors.forename: Inge
authors.initials: I
authors.lastname: Van de Walle
authors.affiliation: Faculty of Medicine and Health Sciences, Department of Clinical Chemistry, Microbiology and Immunology, Ghent University, University Hospital Ghent, 4BlokA, De Pintelaan 185, B-9000 Ghent, Belgium.
authors.forename: Anne-Catherine
authors.initials: AC
authors.lastname: Dolens
authors.affiliation: Center for Medical Genetics, Ghent University, University Hospital Ghent, Medical Research Building 1, De Pintelaan 185, B-9000 Ghent, Belgium.
authors.forename: Kaat
authors.initials: K
authors.lastname: Durinck
authors.affiliation: Faculty of Medicine and Health Sciences, Department of Clinical Chemistry, Microbiology and Immunology, Ghent University, University Hospital Ghent, 4BlokA, De Pintelaan 185, B-9000 Ghent, Belgium.
authors.forename: Katrien
authors.initials: K
authors.lastname: De Mulder
authors.affiliation: Center for Medical Genetics, Ghent University, University Hospital Ghent, Medical Research Building 1, De Pintelaan 185, B-9000 Ghent, Belgium.
authors.forename: Wouter
authors.initials: W
authors.lastname: Van Loocke
authors.affiliation: Division of Biology &Biological Engineering, California Institute of Technology, MC156-29, 1200 East California Boulevard, Pasadena, California 91125, USA.
authors.forename: Sagar
authors.initials: S
authors.lastname: Damle
authors.affiliation: Faculty of Medicine and Health Sciences, Department of Clinical Chemistry, Microbiology and Immunology, Ghent University, University Hospital Ghent, 4BlokA, De Pintelaan 185, B-9000 Ghent, Belgium.
authors.forename: Els
authors.initials: E
authors.lastname: Waegemans
authors.affiliation: Faculty of Medicine and Health Sciences, Department of Clinical Chemistry, Microbiology and Immunology, Ghent University, University Hospital Ghent, 4BlokA, De Pintelaan 185, B-9000 Ghent, Belgium.
authors.forename: Jelle
authors.initials: J
authors.lastname: De Medts
authors.affiliation: Faculty of Medicine and Health Sciences, Department of Clinical Chemistry, Microbiology and Immunology, Ghent University, University Hospital Ghent, 4BlokA, De Pintelaan 185, B-9000 Ghent, Belgium.
authors.forename: Imke
authors.initials: I
authors.lastname: Velghe
authors.affiliation: Faculty of Medicine and Health Sciences, Department of Clinical Chemistry, Microbiology and Immunology, Ghent University, University Hospital Ghent, 4BlokA, De Pintelaan 185, B-9000 Ghent, Belgium.
authors.forename: Magda
authors.initials: M
authors.lastname: De Smedt
authors.affiliation: Faculty of Medicine and Health Sciences, Department of Clinical Chemistry, Microbiology and Immunology, Ghent University, University Hospital Ghent, 4BlokA, De Pintelaan 185, B-9000 Ghent, Belgium.
authors.forename: Bart
authors.initials: B
authors.lastname: Vandekerckhove
authors.affiliation: Faculty of Medicine and Health Sciences, Department of Clinical Chemistry, Microbiology and Immunology, Ghent University, University Hospital Ghent, 4BlokA, De Pintelaan 185, B-9000 Ghent, Belgium.
authors.forename: Tessa
authors.initials: T
authors.lastname: Kerre
authors.affiliation: Faculty of Medicine and Health Sciences, Department of Clinical Chemistry, Microbiology and Immunology, Ghent University, University Hospital Ghent, 4BlokA, De Pintelaan 185, B-9000 Ghent, Belgium.
authors.forename: Jean
authors.initials: J
authors.lastname: Plum
authors.affiliation: Faculty of Medicine and Health Sciences, Department of Clinical Chemistry, Microbiology and Immunology, Ghent University, University Hospital Ghent, 4BlokA, De Pintelaan 185, B-9000 Ghent, Belgium.
authors.forename: Georges
authors.initials: G
authors.lastname: Leclercq
authors.affiliation: Division of Biology &Biological Engineering, California Institute of Technology, MC156-29, 1200 East California Boulevard, Pasadena, California 91125, USA.
authors.forename: Ellen V
authors.initials: EV
authors.lastname: Rothenberg
authors.affiliation: Center for Medical Genetics, Ghent University, University Hospital Ghent, Medical Research Building 1, De Pintelaan 185, B-9000 Ghent, Belgium.
authors.forename: Pieter
authors.initials: P
authors.lastname: Van Vlierberghe
authors.affiliation: Center for Medical Genetics, Ghent University, University Hospital Ghent, Medical Research Building 1, De Pintelaan 185, B-9000 Ghent, Belgium.
authors.forename: Frank
authors.initials: F
authors.lastname: Speleman
authors.affiliation: Faculty of Medicine and Health Sciences, Department of Clinical Chemistry, Microbiology and Immunology, Ghent University, University Hospital Ghent, 4BlokA, De Pintelaan 185, B-9000 Ghent, Belgium.
authors.forename: Tom
authors.initials: T
authors.lastname: Taghon
mesh_terms: D002454:Cell Differentiation; D019070:Cell Lineage / Q000235:genetics* / Q000276:immunology; D065150:Cellular Reprogramming; D002648:Child; D025461:Feedback, Physiological; D050990:GATA3 Transcription Factor / Q000235:genetics* / Q000276:immunology; D018507:Gene Expression Regulation, Developmental; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000276:immunology*; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000235:genetics / Q000276:immunology; D006801:Humans; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology; D061251:Primary Cell Culture; D051881:Receptor, Notch1 / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D060168:Thymocytes / Q000166:cytology / Q000276:immunology*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000276:immunology
chemical_list: D050990:GATA3 Transcription Factor; C494749:GATA3 protein, human; C496487:HNF1A protein, human; D051538:Hepatocyte Nuclear Factor 1-alpha; C497761:NOTCH1 protein, human; D051881:Receptor, Notch1; C583410:DTX1 protein, human; D044767:Ubiquitin-Protein Ligases