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Transcription factor expression dynamics of early T-lymphocyte specification and commitment

David-Fung, Elizabeth-Sharon and Butler, Robert and Buzi, Gentian and Yui, Mary A. and Diamond, Rochelle A. and Anderson, Michele K. and Rowen, Lee and Rothenberg, Ellen V. (2009) Transcription factor expression dynamics of early T-lymphocyte specification and commitment. Developmental Biology, 325 (2). pp. 444-467. ISSN 0012-1606. PMCID PMC2663971.

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Mammalian T lymphocytes are a prototype for development from adult pluripotent stem cells. While T-cell specification is driven by Notch signaling, T-lineage commitment is only finalized after prolonged Notch activation. However, no T-lineage specific regulatory factor has been reported that mediates commitment. We used a gene-discovery approach to identify additional candidate T-lineage transcription factors and characterized expression of > 100 regulatory genes in early T-cell precursors using realtime RT-PCR. These regulatory genes were also monitored in multilineage precursors as they entered T-cell or non-T-cell pathways in vitro; in non-T cells ex vivo; and in later T-cell developmental stages after lineage commitment. At least three major expression patterns were observed. Transcription factors in the largest group are expressed at relatively stable levels throughout T-lineage specification as a legacy from prethymic precursors, with some continuing while others are downregulated after commitment. Another group is highly expressed in the earliest stages only, and is downregulated before or during commitment. Genes in a third group undergo upregulation at one of three distinct transitions, suggesting a positive regulatory cascade. However, the transcription factors induced during commitment are not T-lineage specific. Different members of the same transcription factor family can follow opposite trajectories during specification and commitment, while factors co-expressed early can be expressed in divergent patterns in later T-cell development. Some factors reveal new regulatory distinctions between αβ and γδ T-lineage differentiation. These results show that T-cell identity has an essentially complex regulatory basis and provide a detailed framework for regulatory network modeling of T-cell specification.

Item Type:Article
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URLURL TypeDescription CentralArticle
Buzi, Gentian0000-0002-8724-3405
Yui, Mary A.0000-0002-3136-2181
Rothenberg, Ellen V.0000-0002-3901-347X
Additional Information:© 2009 Elsevier. Received 16 September 2008; accepted 17 October 2008. Available online 5 November 2008. We are deeply indebted to Dr. Howard Petrie (Scripps Florida) for valuable discussions during the gestation of this work and for generous sharing of data prior to publication. We are also grateful to Dr. Hamid Bolouri (Caltech and Institute for Systems Biology) and Dr. Eric Davidson (Caltech) for insightful critiques, encouragement, and advice. We also thank Brian Birditt and Scott Bloom (Institute for Systems Biology) for their excellent work sequencing and identifying the cDNA clones from our gene discovery; Marissa Morales and Dr. Rashmi Pant, for key contributions to the gene expression measurements and their validation; Dr. Tom Taghon, for generous collaboration on making the samples for the OP9 experiments; Gillian Giorgio, for early help curating the sequence files; Stephanie Adams of the Caltech Flow Cytometry Facility, for outstanding help with the sorting; and Robin Condie and Ruben Bayon for excellent care of the animals. This work was undertaken with support from the Stowers Institute for Medical Research and then supported by grants from the NSF (MCB9983129) and the NIH (R01 CA90233 and R33 HL089123), and by the Louis A. Garfinkle Memorial Laboratory Fund, the Al Sherman Fund, the Albert Billings Ruddock Professorship, and the DNA Sequencer Royalty Fund at Caltech.
Funding AgencyGrant Number
Stowers Institute for Medical ResearchUNSPECIFIED
NIHR01 CA90233
NIHR33 HL089123
Louis A. Garfinkle Memorial Laboratory FundUNSPECIFIED
Albert Billings Ruddock ProfessorshipUNSPECIFIED
DNA Sequencer Royalty Fund, CaltechUNSPECIFIED
Subject Keywords:T-cell development; Notch; Thymus; Lineage commitment; Hematopoiesis
Issue or Number:2
PubMed Central ID:PMC2663971
Record Number:CaltechAUTHORS:20090708-093942975
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Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:14516
Deposited By: Tony Diaz
Deposited On:10 Aug 2009 23:58
Last Modified:09 Mar 2020 13:18

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