Transformation of Accessible Chromatin and 3D Nucleome Underlies Lineage Commitment of Early T Cells
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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 and lose accessibility during commitment.
“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]
The Results section, “Regulome reorganization is associated to T cell commitment” (page unavailable), says sites losing accessibility in earlier stages were specifically enriched for the PU.1 binding motif. It does not establish that PU.1 was the most highly enriched of all defined motifs. (LLM, conf=0.83)
Experimental — accuracy not yet measuredThe transition at commitment includes general downregulation of phase 1 genes and major reorganization of active chromatin and chromatin interactions genome-wide.
“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-citation
- 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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