Bcl11b and combinatorial resolution of cell fate in the T-cell gene regulatory network
Open accessAbstract
T-cell development from hematopoietic progenitors depends on multiple transcription factors, mobilized and modulated by intrathymic Notch signaling. Key aspects of T-cell specification network architecture have been illuminated through recent reports defining roles of transcription factors PU.1, GATA-3, and E2A, their interactions with Notch signaling, and roles of Runx1, TCF-1, and Hes1, providing bases for a comprehensively updated model of the T-cell specification gene regulatory network presented herein. However, the role of lineage commitment factor Bcl11b has been unclear. We use self-organizing maps on 63 RNA-seq datasets from normal and perturbed T-cell development to identify functional targets of Bcl11b during commitment and relate them to other regulomes. We show that both activation and repression target genes can be bound by Bcl11b in vivo, and that Bcl11b effects overlap with E2A-dependent effects. The newly clarified role of Bcl11b distinguishes discrete components of commitment, resolving how innate lymphoid, myeloid, and dendritic, and B-cell fate alternatives are excluded by different mechanisms.
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PU.1 is not uniquely responsible for the Phase 1 gene expression pattern; other Phase 1 genes are either unaffected or moderately inhibited by PU.1.
“PU.1 is not uniquely responsible for the Phase 1 gene expression pattern, however, for other Phase 1 genes are either unaffected or moderately inhibited by PU.1, as discussed elsewhere (79, 123).”
From Mechanisms of Action of Hematopoietic Transcription Factor PU.1 in Initiation of T-Cell Development (2019) · cites this paper as [123]
In “Explaining Bcl11b Impact on Development” (page unavailable), the paper finds that PU.1-dependent genes form a subset of early-expressed genes and that PU.1 and Bcl11b provide mostly orthogonal inputs. It also reports weak PU.1 repression of Kit, but does not establish that the other Phase 1 genes are generally unaffected or moderately inhibited by PU.1. (LLM, conf=0.78)
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References 63 · Cited by 89
Research works printed but not linked: 48
- Kueh HY, et al. (2016) Asynchronous combinatorial action of four regulatory factors activates Bcl11b for T cell commitment. Nat Immunol 17(8):956-965.
- Li L, Leid M, Rothenberg EV (2010) An early T cell lineage commitment checkpoint dependent on the transcription factor Bcl11b. Science 329(5987):89-93.
- Ikawa T, et al. (2010) An essential developmental checkpoint for production of the T cell lineage. Science 329(5987):93-96.
- Yui MA, Rothenberg EV (2014) Developmental gene networks: A triathlon on the course to T cell identity. Nat Rev Immunol 14(8):529-545.
- Yui MA, Feng N, Rothenberg EV (2010) Fine-scale staging of T cell lineage commit- ment in adult mouse thymus. J Immunol 185(1):284-293.
- Mingueneau M, et al.; Immunological Genome Consortium (2013) The transcriptional landscape of αβ T cell differentiation. Nat Immunol 14(6):619-632.
- Avram D, Califano D (2014) The multifaceted roles of Bcl11b in thymic and peripheral T cells: Impact on immune diseases. J Immunol 193(5):2059-2065.
- Califano D, et al. (2015) Transcription factor Bcl11b controls identity and function of mature type 2 innate lymphoid cells. Immunity 43(2):354-368.
- Albu DI, et al. (2007) BCL11B is required for positive selection and survival of double- positive thymocytes. J Exp Med 204(12):3003-3015.
- Kastner P, et al. (2010) Bcl11b represses a mature T-cell gene expression program in immature CD4 (+) CD8 (+) thymocytes. Eur J Immunol 40(8):2143-2154.
- Kohonen T (2001) Self-Organizing Maps (Springer, New York).
- Golub TR, et al. (1999) Molecular classification of cancer: Class discovery and class prediction by gene expression monitoring. Science 286(5439):531-537.
- Spencer WC, et al. (2011) A spatial and temporal map of C. elegans gene expression. Genome Res 21(2):325-341.
- Mortazavi A, et al. (2013) Integrating and mining the chromatin landscape of cell- type specificity using self-organizing maps. Genome Res 23(12):2136-2148.
- Kueh HY, Rothenberg EV (2012) Regulatory gene network circuits underlying T cell de- velopment from multipotent progenitors. Wiley Interdiscip Rev Syst Biol Med 4(1):79-102.
- Georgescu C, et al. (2008) A gene regulatory network armature for T lymphocyte specification. Proc Natl Acad Sci USA 105(51):20100-20105.
- Rothenberg EV, Anderson MK (2002) Elements of transcription factor network design for T-lineage specification. Dev Biol 246(1):29-44.
- Del Real MM, Rothenberg EV (2013) Architecture of a lymphomyeloid developmental switch controlled by PU.1, Notch and Gata3. Development 140(6):1207-1219.
- Xu W, et al. (2013) E2A transcription factors limit expression of Gata3 to facilitate T lymphocyte lineage commitment. Blood 121(9):1534-1542.
- De Obaldia ME, et al. (2013) T cell development requires constraint of the myeloid regulator C/EBP-α by the Notch target and transcriptional repressor Hes1. Nat Immunol 14(12):1277-1284.
- Laiosa CV, Stadtfeld M, Xie H, de Andres-Aguayo L, Graf T (2006) Reprogramming of committed T cell progenitors to macrophages and dendritic cells by C/EBP α and PU.1 transcription factors. Immunity 25(5):731-744.
- García-Ojeda ME, et al. (2013) GATA-3 promotes T-cell specification by repressing B-cell potential in pro-T cells in mice. Blood 121(10):1749-1759.
- Banerjee A, Northrup D, Boukarabila H, Jacobsen SE, Allman D (2013) Transcriptional repression of Gata3 is essential for early B cell commitment. Immunity 38(5):930-942.
- Li L, et al. (2013) A far downstream enhancer for murine Bcl11b controls its T-cell specific expression. Blood 122(6):902-911.
- Walker JA, et al. (2015) Bcl11b is essential for group 2 innate lymphoid cell devel- opment. J Exp Med 212(6):875-882.
- Yu Y, et al. (2015) The transcription factor Bcl11b is specifically expressed in group 2 innate lymphoid cells and is essential for their development. J Exp Med 212(6):865-874.
- Hoogenkamp M, et al. (2007) The Pu.1 locus is differentially regulated at the level of chromatin structure and noncoding transcription by alternate mechanisms at distinct developmental stages of hematopoiesis. Mol Cell Biol 27(21):7425-7438.
- Wakabayashi Y, et al. (2003) Bcl11b is required for differentiation and survival of alphabeta T lymphocytes. Nat Immunol 4(6):533-539.
- Schmitt TM, Zúñiga-Pflücker JC (2002) Induction of T cell development from hema- topoietic progenitor cells by delta-like-1 in vitro. Immunity 17(6):749-756.
- Koues OI, et al. (2016) Distinct gene regulatory pathways for human innate versus adaptive lymphoid cells. Cell 165(5):1134-1146.
- Seillet C, et al. (2016) Deciphering the innate lymphoid cell transcriptional program. Cell Reports 17(2):436-447.
- Heng TSP, Painter MW; Immunological Genome Project Consortium (2008) The Im- munological Genome Project: Networks of gene expression in immune cells. Nat Immunol 9(10):1091-1094.
- Rothenberg EV, Kueh HY, Yui MA, Zhang JA (2016) Hematopoiesis and T-cell speci- fication as a model developmental system. Immunol Rev 271(1):72-97.
- Miyazaki M, et al. (2011) The opposing roles of the transcription factor E2A and its antagonist Id3 that orchestrate and enforce the naive fate of T cells. Nat Immunol 12(10):992-1001.
- Ikawa T, Kawamoto H, Goldrath AW, Murre C (2006) E proteins and Notch signaling cooperate to promote T cell lineage specification and commitment. J Exp Med 203(5): 1329-1342.
- Jones ME, Zhuang Y (2011) Stage-specific functions of E-proteins at the β-selection and T-cell receptor checkpoints during thymocyte development. Immunol Res 49(1-3): 202-215.
- Constantinides MG, et al. (2015) PLZF expression maps the early stages of ILC1 lineage development. Proc Natl Acad Sci USA 112(16):5123-5128.
- Seillet C, et al. (2014) Nfil3 is required for the development of all innate lymphoid cell subsets. J Exp Med 211(9):1733-1740.
- Seillet C, et al. (2014) Differential requirement for Nfil3 during NK cell development. J Immunol 192(6):2667-2676.
- Serafini N, Vosshenrich CA, Di Santo JP (2015) Transcriptional regulation of innate lymphoid cell fate. Nat Rev Immunol 15(7):415-428.
- Xu W, et al. (2015) NFIL3 orchestrates the emergence of common helper innate lymphoid cell precursors. Cell Reports 10(12):2043-2054.
- Ishizuka IE, et al. (2016) Single-cell analysis defines the divergence between the in- nate lymphoid cell lineage and lymphoid tissue-inducer cell lineage. Nat Immunol 17(3):269-276.
- Diefenbach A, Colonna M, Koyasu S (2014) Development, differentiation, and di- versity of innate lymphoid cells. Immunity 41(3):354-365.
- Robinette ML, et al.; Immunological Genome Consortium (2015) Transcriptional programs define molecular characteristics of innate lymphoid cell classes and subsets. Nat Immunol 16(3):306-317.
- Cohen NR, et al.; ImmGen Project Consortium (2013) Shared and distinct transcrip- tional programs underlie the hybrid nature of iNKT cells. Nat Immunol 14(1):90-99.
- Constantinides MG, McDonald BD, Verhoef PA, Bendelac A (2014) A committed precursor to innate lymphoid cells. Nature 508(7496):397-401.
- Shih HY, et al. (2016) Developmental acquisition of regulomes underlies innate lymphoid cell functionality. Cell 165(5):1120-1133.
- Longabaugh WJR, Davidson EH, Bolouri H (2005) Computational representation of developmental genetic regulatory networks. Dev Biol 283(1):1-16.
- Authors
- Longabaugh, W. J. R., Zeng, W., Zhang, J. A., Hosokawa, H., Jansen, C. S., Li, L., Romero-Wolf, M., Liu, P., Kueh, H. Y., Mortazavi, A., & Rothenberg, E. V.
- Affiliations
- Institute for Systems Biology (US)
- University of California, Irvine (US)
- California Institute of Technology (US)
- Wellcome/MRC Cambridge Stem Cell Institute (GB)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2017-06-05
- Volume
- 114
- Issue
- 23
- Pages
- 5800-5807
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC5468679
- OpenAlex
- W2624618144
- Cited by
- 89
- References
- 63
- Citations by year
- 2026: 2 · 2025: 6 · 2024: 8 · 2023: 6 · 2022: 8 · 2021: 12 · 2020: 12 · 2019: 16 · 2018: 12 · 2017: 7
- FWCI
- 5.82
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- CaltechAUTHORS (California Institute of Technology) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- The HKU Scholars Hub (University of Hong Kong) (submittedVersion)
- Funders
- HHS | NIH | National Institute of Child Health and Human Development (R01HD073113)
- HHS | NIH | National Heart, Lung, and Blood Institute (K99HL119638A)
- HHS | NIH | National Institute of Allergy and Infectious Diseases (R01AI083514, R01AI95943)
- HHS | NIH | National Cancer Institute (RC2CA148278, R01CA90233)
- HHS | NIH | National Institute of General Medical Sciences (DP2GM111100)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- BCL11B, T cell development, gene regulatory networks, lineage commitment, Notch signaling, E2A, transcription factors, PU.1, GATA3, RUNX1, TCF1, Hes1, self-organizing maps, RNA-seq, transcriptional repression
- MeSH terms
- Animals, Cell Differentiation, Mice, Inbred C57BL, Repressor Proteins, T-Lymphocytes, Signal Transduction, Mice, Knockout, Tumor Suppressor Proteins, Mice, Receptors, Notch, Gene Regulatory Networks
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