TCF1 dosage determines cell fate during T cell development
Loss-of-function studies have shown that transcription factor T cell factor-1 (TCF1), encoded by the <i>Tcf7</i> gene, is essential for T cell development in the thymus. We discovered that the <i>Tcf7</i> expression level is regulated by E box DNA binding proteins, independent of Notch, and regulates αβ and γδ T cell development. Systematic interrogation of the five E protein binding elements (EPE1-5) in the <i>Tcf7</i> enhancer region showed lineage-specific utilization. Specifically, loss-of-function analysis revealed that only EPE3 plays a critical role in supporting αβ T cell development, while EPE1, 3, and 5 regulate the γδ T cell maturation and functional cell fate decision. The importance of EPE3 in supporting both lineages may stem from its unique capacity to interact with the <i>Tcf7</i> transcriptional start site. Together, these studies demonstrate that the precise dosage of TCF1 expression mediated by distinct EPEs generates a balanced output of T cells from the thymus.
Authors
- David L. Wiest (ORCID: https://orcid.org/0000-0002-0792-3188)
- Byron Koenitzer (ORCID: https://orcid.org/0009-0004-1861-8711)
- Susan A. Shinton (ORCID: https://orcid.org/0000-0003-2649-1904)
- Bridget Aylward (ORCID: https://orcid.org/0000-0002-0377-2028)
- Supriyo De (ORCID: https://orcid.org/0000-0002-2075-7655)
- Laura B. Chopp (ORCID: https://orcid.org/0000-0001-6494-4439)
- Rémy Bosselut (ORCID: https://orcid.org/0000-0003-2033-1790)
- Fei Ma (ORCID: https://orcid.org/0000-0003-0401-0954)
- Xiang Qiu (ORCID: https://orcid.org/0000-0001-9161-9033)
- Alejandra Contreras (ORCID: https://orcid.org/0000-0003-3653-5958)
- Krystyna Mazan-Mamczarz (ORCID: https://orcid.org/0009-0005-1545-0500)
- Cheryl A. Sherman‐Baust (ORCID: https://orcid.org/0000-0001-7977-4698)
- Shawn P. Fahl (ORCID: https://orcid.org/0000-0002-0489-2048)
- Noah Ollikainen (ORCID: https://orcid.org/0000-0002-1174-2400)
- Parirokh Awasthi (ORCID: https://orcid.org/0000-0002-5831-9781)
- Anjali Verma (ORCID: https://orcid.org/0009-0001-0225-7331)
- Ranjan Sen (ORCID: https://orcid.org/0000-0002-1916-3905)
- Roshni Roy
- Jyoti Misra Sen (ORCID: https://orcid.org/0000-0002-6365-0866)
Institutions
- Fox Chase Cancer Center (US)
- National Institutes of Health (US)
- Johns Hopkins University (US)
- Johns Hopkins Medicine (US)
- Frederick National Laboratory for Cancer Research (US)
- National Institute on Aging (US)
- National Cancer Institute (US)
- Center for Cancer Research (US)
Publication Details
- Journal
- Science Advances
- Published
- 2024-11-27
- DOI
- https://doi.org/10.1126/sciadv.ado5982
- Citations
- 3
- Primary Topic
- T-cell and B-cell Immunology
- Type
- article
- Field-Weighted Citation Impact
- 0.72