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Transformation of Accessible Chromatin and 3D Nucleome Underlies Lineage Commitment of Early T Cells
Open accessAbstract
How chromatin reorganization coordinates differentiation and lineage commitment from hematopoietic stem and progenitor cells (HSPCs) to mature immune cells has not been well understood. Here, we carried out an integrative analysis of chromatin accessibility, topologically associating domains, AB compartments, and gene expression from HSPCs to CD4+CD8+ T cells. We found that abrupt genome-wide changes at all three levels of chromatin organization occur during the transition from double-negative stage 2 (DN2) to DN3, accompanying the T lineage commitment. The transcription factor BCL11B, a critical regulator of T cell commitment, is associated with increased chromatin interaction, and Bcl11b deletion compromised chromatin interaction at its target genes. We propose that these large-scale and concerted changes in chromatin organization present an energy barrier to prevent the cell from reversing its fate to earlier stages or redirecting to alternatives and thus lock the cell fate into the T lineages.
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“PU.1 recognition motifs are the most highly enriched of all defined motifs at sites that start out highly accessible in early pro-T cell stages, when PU.1 is present, and lose accessibility during commitment, i.e., as PU.1 levels decline (44, 85, 95).”
From Mechanisms of Action of Hematopoietic Transcription Factor PU.1 in Initiation of T-Cell Development (2019) · cites this paper as [44]
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“This is part of a general downregulation of stem/progenitor associated regulatory genes (“phase 1 genes”) (34, 43) and a major reorganization of active chromatin and chromatin interactions, genome-wide, that occurs during this transition (44).”
From Mechanisms of Action of Hematopoietic Transcription Factor PU.1 in Initiation of T-Cell Development (2019) · cites this paper as [44]
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Self-citationEpigenetics changes during allergen immunotherapy – Review of available literature
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Additional file 5 of Co-localization of clusters of TCR-regulated genes with TAD rearrangements
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Additional file 2 of Co-localization of clusters of TCR-regulated genes with TAD rearrangements
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Additional file 4 of Co-localization of clusters of TCR-regulated genes with TAD rearrangements
Gao, G. F., Li, P., & Leonard, W. J. (2024) · Figshare · doi:10.6084/m9.figshare.26633649
Mahmood, S. R., Said, N. H. E., Gunsalus, K. C., & Percipalle, P. (2024) · Figshare · doi:10.6084/m9.figshare.26564031
Additional file 3 of Co-localization of clusters of TCR-regulated genes with TAD rearrangements
Gao, G. F., Li, P., & Leonard, W. J. (2024) · Figshare · doi:10.6084/m9.figshare.26633646
Additional file 6 of Co-localization of clusters of TCR-regulated genes with TAD rearrangements
Gao, G. F., Li, P., & Leonard, W. J. (2024) · Figshare · doi:10.6084/m9.figshare.26633655
Mahmood, S. R., Said, N. H. E., Gunsalus, K. C., & Percipalle, P. (2024) · Figshare · doi:10.6084/m9.figshare.26564034
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Self-citationAdditional file 1 of Co-localization of clusters of TCR-regulated genes with TAD rearrangements
Gao, G. F., Li, P., & Leonard, W. J. (2023) · Figshare · doi:10.6084/m9.figshare.24454921
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Metadata
- Authors
- Hu, G., Cui, K., Fang, D., Hirose, S., Wang, X., Wangsa, D., Jin, W., Ried, T., Liu, P., Zhu, J., Rothenberg, E. V., & Zhao, K.
- Affiliations
- National Institutes of Health (US)
- California Institute of Technology (US)
- Wellcome Sanger Institute (GB)
- Corresponding author
- Hu, Gangqing
- Rothenberg, Ellen V.
- Zhao, Keji
- ORCID
- Venue
- Immunity
- Publisher
- Elsevier BV
- Published
- 2018-02
- Volume
- 48
- Issue
- 2
- Pages
- 227-242.e8
- ISSN
- 1074-7613 (ISSN-L)
- PMC
- PMC5847274
- OpenAlex
- W2788037203
- Cited by
- 199
- References
- 70
- Citations by year
- 2026: 5 · 2025: 11 · 2024: 15 · 2023: 40 · 2022: 33 · 2021: 34 · 2020: 24 · 2019: 27 · 2018: 10
- FWCI
- 8.45
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Immunity (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- CaltechAUTHORS (California Institute of Technology) (submittedVersion)
- Funders
- Division of Intramural Research of the National Cancer Institute
- National Institute of Allergy and Infectious Diseases
- NHLBI
- NIH (R01 AI083514)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- 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
- Keywords
- T cell lineage commitment, chromatin accessibility, 3D genome organization, topologically associating domains, A/B compartments, hematopoietic stem and progenitor cells, double-negative T cells, BCL11B, chromatin interactions, cell fate determination, T cell differentiation
- MeSH terms
- Animals, Cell Differentiation, Cell Nucleus, Chromatin, Humans, Repressor Proteins, T-Lymphocytes, Cell Lineage, Tumor Suppressor Proteins
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