GATA-3 Dose-Dependent Checkpoints in Early T Cell Commitment
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GATA-3 expression is crucial for T cell development and peaks during commitment to the T cell lineage, midway through the CD4−CD8− (double-negative [DN]) stages 1–3. We used RNA interference and conditional deletion to reduce GATA-3 protein acutely at specific points during T cell differentiation in vitro. Even moderate GATA-3 reduction killed DN1 cells, delayed progression to the DN2 stage, skewed DN2 gene regulation, and blocked appearance of the DN3 phenotype. Although a Bcl-2 transgene rescued DN1 survival and improved DN2 cell generation, it did not restore DN3 differentiation. Gene expression analyses (quantitative PCR, RNA sequencing) showed that GATA-3–deficient DN2 cells quickly upregulated genes, including Spi1 (PU.1) and Bcl11a, and downregulated genes, including Cpa3, Ets1, Zfpm1, Bcl11b, Il9r, and Il17rb with gene-specific kinetics and dose dependencies. These targets could mediate two distinct roles played by GATA-3 in lineage commitment, as revealed by removing wild-type or GATA-3–deficient early T lineage cells from environmental Notch signals. GATA-3 worked as a potent repressor of B cell potential even at low expression levels, so that only full deletion of GATA-3 enabled pro–T cells to reveal B cell potential. The ability of GATA-3 to block B cell development did not require T lineage commitment factor Bcl11b. In prethymic multipotent precursors, however, titration of GATA-3 activity using tamoxifen-inducible GATA-3 showed that GATA-3 inhibits B and myeloid developmental alternatives at different threshold doses. Furthermore, differential impacts of a GATA-3 obligate repressor construct imply that B and myeloid development are inhibited through distinct transcriptional mechanisms. Thus, the pattern of GATA-3 expression sequentially produces B lineage exclusion, T lineage progression, and myeloid-lineage exclusion for commitment.
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The earliest fetal thymocytes are different from later waves of developing thymocytes in their abilities to generate particular classes of TCRγδ cells and in their extremely fast differentiation kinetics, both in vivo and in fetal thymic organ culture or stromal coculture systems.
“It has long been recognized that the earliest fetal thymocytes are different from later waves of developing thymocytes in terms of their abilities to generate particular classes of TCRγδ cells (134) and in terms of their extremely fast differentiation kinetics, both in vivo and in fetal thymic organ culture or stromal coculture systems (104, 133, 135).”
From Mechanisms of Action of Hematopoietic Transcription Factor PU.1 in Initiation of T-Cell Development (2019) · cites this paper as [104]
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Experimental — accuracy not yet measuredThe best current candidates for this silencing activity include GATA-3, TCF-1 or LEF-1, and especially Runx1, probably working in a dose-dependent combination, although the mechanism through which they finally achieve the ability to repress PU.1 has not yet been reported.
“The best current candidates for this silencing activity include GATA-3 (104, 105), TCF-1 or LEF-1 (37), and especially Runx1 (80, 150–152), probably working in a dose-dependent combination, although the mechanism through which they finally achieve the ability to repress PU.1 has not yet been reported.”
From Mechanisms of Action of Hematopoietic Transcription Factor PU.1 in Initiation of T-Cell Development (2019) · cites this paper as [104]
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Hematopoiesis and T‐cell specification as a model developmental system
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Self-citationSingle-cell insights into the hematopoietic generation of T-lymphocyte precursors in mouse and human
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The Hematopoietic Stem and Progenitor Cell Cistrome
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Transcriptional network dynamics in early T cell development
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Self-citationInsights into Thymus Development and Viral Thymic Infections
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3D Genome Organization as an Epigenetic Determinant of Transcription Regulation in T Cells
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Stage-specific action of Runx1 and GATA3 controls silencing of PU.1 expression in mouse pro–T cells
Hosokawa, H., Koizumi, M., Masuhara, K., Romero-Wolf, M., Tanaka, T., Nakayama, T., & Rothenberg, E. V. (2021) · The Journal of Experimental Medicine · doi:10.1084/jem.20202648 · Cited by 22 · see citing works
Self-citationLogic and lineage impacts on functional transcription factor deployment for T-cell fate commitment
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Self-citationGlobal dynamics of stage-specific transcription factor binding during thymocyte development
Hosoya, T., Albanus, R. D., Hensley, J., Myers, G., Kyono, Y., Kitzman, J. O., Parker, S. C. J., & Engel, J. D. (2018) · Scientific Reports · doi:10.1038/s41598-018-23774-9 · Cited by 17 · see citing works
NKL homeobox gene NKX2-2 is aberrantly expressed in Hodgkin lymphoma
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Speed and navigation control of thymocyte development by the fetal T‐cell gene regulatory network
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Self-citationDynamic control of the T-cell specification gene regulatory network
Rothenberg, E. V. (2019) · Current Opinion in Systems Biology · doi:10.1016/j.coisb.2019.10.012 · Cited by 16 · see citing works
Self-citationOlariu, V., Yui, M. A., Krupinski, P., Zhou, W., Deichmann, J., Andersson, E., Rothenberg, E. V., & Peterson, C. (2021) · Cell Reports · doi:10.1016/j.celrep.2020.108622 · Cited by 15 · see citing works
Self-citationA monoallelic-to-biallelic T-cell transcriptional switch regulates GATA3 abundancePreprint
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Self-citationRothenberg, E. V., Champhekar, A. S., Damle, S. S., Real, M. M. D., Kueh, H. Y., Li, L., & Yui, M. A. (2013) · Cold Spring Harbor Symposia on Quantitative Biology · doi:10.1101/sqb.2013.78.020271 · Cited by 13 · see citing works
Self-citationGATA3: Orchestrating cellular fate through differentiation and proliferation
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Logical modeling of cell fate specification—Application to T cell commitment
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Gata3 restrains B cell proliferation and cooperates with p18INK4c to repress B cell lymphomagenesis
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The Role of NOTCH1, GATA3, and c-MYC in T Cell Non-Hodgkin Lymphomas
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E Protein Transcription Factors as Suppressors of T Lymphocyte Acute Lymphoblastic Leukemia
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GATA3 Abundance Is a Critical Determinant of T Cell Receptor β Allelic Exclusion
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Thymic mast cells: at three-way crossroads
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Fitting structure to function in gene regulatory networks
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Self-citationNew Insights of Human Parvovirus B19 in Modulating Erythroid Progenitor Cell Differentiation
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Gene-regulatory programs that specify age-related differences during thymocyte development
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Notch interaction with RUNX factors regulates initiation of the T-lineage program
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T-cell commitment inheritance—an agent-based multi-scale model
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Self-citationNew Insights of Human Parvovirus B19 in Modulating Erythroid Progenitor Cells DifferentiationPreprint
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Transcriptional Regulation of T Cell Lineage Commitment
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E-proteins set the threshold for optimal TCF1 expression during αβ T cell developmentPreprint
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T-cell commitment inheritance – an agent-based multi-scale modelPreprint
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Transcriptional Regulation of T-Cell Lineage Commitment
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Self-citationNotch Functions in T Cell Development
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The long non-coding RNA Dreg1 is required for optimal ILC2 development
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The long non-coding RNA Dreg1 is required for optimal ILC2 developmentPreprint
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The long non-coding RNA Dreg1 is required for optimal ILC2 developmentPreprint
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Bcl11b dose-dependently regulates positive selection of CD8 T cells to the virtual memory fatePreprint
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Self-citation
- Authors
- Scripture-Adams, D. D., Damle, S. S., Li, L., Elihu, K. J., Qin, S., Arias, A. M., Butler, R. R., Champhekar, A., Zhang, J. A., & Rothenberg, E. V.
- Affiliations
- California Institute of Technology (US)
- Corresponding author
- Rothenberg, Ellen V
- ORCID
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2014-10-01
- Volume
- 193
- Issue
- 7
- Pages
- 3470-3491
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- PMC
- PMC4170028
- OpenAlex
- W1823105344
- Cited by
- 81
- References
- 57
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 6 · 2023: 4 · 2022: 6 · 2021: 8 · 2020: 9 · 2019: 12 · 2018: 8 · 2017: 5 · 2016: 9 · 2015: 5 · 2014: 1 · 2013: 1
- FWCI
- 3.05
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- CaltechAUTHORS (California Institute of Technology) (submittedVersion)
- Funders
- National Cancer Institute (R01CA98925, R01CA90233, R01CA090233, RC2CA148278, R01CA098925)
- National Institute of Allergy and Infectious Diseases (R01AI95943, R01AI095943)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (5T32HD07257, T32HD007257)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- GATA3, T cell development, T cell lineage commitment, double-negative thymocytes, BCL11B, Bcl-2, Notch signaling, transcriptional repression, PU.1, BCL11A, conditional gene deletion
- MeSH terms
- Animals, Cell Line, Repressor Proteins, Tamoxifen, Signal Transduction, Up-Regulation, Antineoplastic Agents, Hormonal, Proto-Oncogene Proteins c-bcl-2, Myeloid Cells, Tumor Suppressor Proteins, GATA3 Transcription Factor, Mice, Receptors, Notch, Precursor Cells, T-Lymphoid
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