Dual Functions of T-Box 3 (Tbx3) in the Control of Self-renewal and Extraembryonic Endoderm Differentiation in Mouse Embryonic Stem Cells
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Embryonic stem cells (ESCs) possess the capacity to proliferate indefinitely in an undifferentiated state and to differentiate into various cell types in an organism. However, the critical question of how self-renewal and differentiation are precisely regulated in ESCs is not entirely understood at present. Here, we report the essential role of Tbx3, a pluripotency-related transcription factor of the T-box gene family, for both the maintenance of self-renewal of mouse ESCs and for their differentiation into extraembryonic endoderm (ExEn). We show that Tbx3 is highly expressed in ExEn cells in addition to undifferentiated ESCs. Knockdown of Tbx3 expression using tetracycline-regulated Tbx3 siRNA resulted in the attenuation of ESC self-renewal ability and aberrant differentiation processes, including reduced ExEn differentiation but enhanced ectoderm and trophectoderm differentiation. Conversely, inducible forced expression of Tbx3 triggered ExEn lineage commitment. Mechanistically, Tbx3 directly activated the expression of Gata6, an essential regulator of ExEn. Interestingly, Tbx3 modulated H3K27me3 modification and the association of the PRC2 complex with the promoter region of Gata6. Taken together, the results of this study revealed a previously unappreciated role of a pluripotency factor in ExEn differentiation. Additionally, our data reveal that Tbx3 may function through direct binding and epigenetic modification of histones on the Gata6 promoter to maintain the ExEn differentiation potential of ESCs.
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TBX3 has been shown to directly promote the expression of target genes by binding to specific DNA sequences within those genes.
“TBX3 has been shown to directly promote the expression of target genes by binding to specific DNA sequences within those genes.”
From TBX3 shapes an immunosuppressive microenvironment and induces immunotherapy resistance (2025) · cites this paper as [78]
Tbx3 directly activates Gata6 expression via its DNA binding activity.
“Tbx3 directly activates Gata6 expression via its DNA binding activity. TBX3 has been shown to directly bind to the promoter of the Gata6 gene, a key regulatory protein of primitive endoderm differentiation, activating the expression of this gene 78.”
From TBX3 shapes an immunosuppressive microenvironment and induces immunotherapy resistance (2025) · cites this paper as [78]
TBX3 is critically involved in pluripotency maintenance and lineage-specific exit from the pluripotency circuitry in mouse embryonic stem cells.
“Finally, TBX3 is not only critically involved in pluripotency maintenance but also in lineage-specific exit from the pluripotency circuitry in mouse embryonic stem cells [11–17].”
From TBX3 is dynamically expressed in pancreatic organogenesis and fine-tunes regeneration (2023) · cites this paper as [17]
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Canonical Wnt Signaling Induces a Primitive Endoderm Metastable State in Mouse Embryonic Stem Cells
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Role of Nuclear Receptor Coactivator 3 (Ncoa3) in Pluripotency Maintenance
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Aberrant GATA2 epigenetic dysregulation induces a GATA2/GATA6 switch in human gastric cancer
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The T-Box transcription factor 3 in development and cancer
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Regulation of organogenesis and stem cell properties by T-box transcription factors
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Factor mediated gene priming in pluripotent stem cells sets the stage for lineage specification
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GATA6 is a regulator of sinus node development and heart rhythm
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Methods for iPS cell generation for basic research and clinical applications
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The SWI/SNF ATP-dependent chromatin remodeling complex in cell lineage priming and early development
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The role of telomere-binding modulators in pluripotent stem cells
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Foxd3 suppresses NFAT‐mediated differentiation to maintain self‐renewal of embryonic stem cells
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Molecular versatility during pluripotency progression
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COL1A2 is a TBX3 target that mediates its impact on fibrosarcoma and chondrosarcoma cell migration
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TBX3, a downstream target of TGF-β1, inhibits mesangial cell apoptosis
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Localized and Temporal Gene Regulation in Heart Development
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Tbx3 represses bmp4 expression and, with Pax6, is required and sufficient for retina formation
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“Multiple oncogenic pathways have been found to regulate TBX3 expression in occurrenceof melanoma,lung, thyroid, breast and other types of cancers 12,15,16,20,21,53,54 , here we de fi ne USP15 as a critical stabilizer for TBX3.”
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A Fresh Look on T-Box Factor Action in Early Embryogenesis (T-Box Factors in Early Development)
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TBX3 shapes an immunosuppressive microenvironment and induces immunotherapy resistance
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Developmental progression continues during embryonic diapause in the roe deer
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A Tale of Two States: Pluripotency Regulation of Telomeres
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Establishment of the TBX-code reveals aberrantly activated T-box gene TBX3 in Hodgkin lymphoma
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TBX3 is dynamically expressed in pancreatic organogenesis and fine-tunes regeneration
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Regulatable In Vivo Biotinylation Expression System in Mouse Embryonic Stem Cells
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Bacterial Ribosomes Induce Plasticity in Mouse Adult Fibroblasts
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Regulation of the cyclin-dependent kinase inhibitor p21 by TBX3
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scMultiPreDICT: A single-cell predictive framework with transcriptomic and epigenetic signaturesPreprint
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T-Box Genes and Developmental Anomalies
Douglas, N. C., Washkowitz, A. J., Naiche, L. A., & Papaioannou, V. E. (2014) · Elsevier eBooks · doi:10.1016/b978-0-12-405945-0.00034-x
- Authors
- Lu, R., Yang, A., & Jin, Y.
- Affiliations
- Shanghai Jiao Tong University (CN)
- Corresponding author
- Jin, Ying
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2011-03
- Volume
- 286
- Issue
- 10
- Pages
- 8425-8436
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC3048727
- OpenAlex
- W1979308978
- Cited by
- 80
- References
- 38
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 6 · 2023: 4 · 2022: 2 · 2021: 6 · 2020: 2 · 2019: 5 · 2018: 5 · 2017: 5 · 2016: 5 · 2015: 6 · 2014: 9 · 2013: 10 · 2012: 8
- FWCI
- 2.61
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Keywords
- TBX3, mouse embryonic stem cells, self-renewal, GATA6, polycomb repressive complex 2, H3K27me3, histone modifications, pluripotency transcription factors, trophectoderm differentiation, ectoderm differentiation, lineage commitment, epigenetic regulation
- MeSH terms
- Animals, Cell Differentiation, Cell Line, Endoderm, Histones, Promoter Regions, Genetic, Protein Processing, Post-Translational, Gene Expression Regulation, Developmental, Cell Lineage, T-Box Domain Proteins, Epigenesis, Genetic, GATA6 Transcription Factor, Mice, Embryonic Stem Cells, Gene Knockdown Techniques
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