Definition of Regulatory Network Elements for T Cell Development by Perturbation Analysis with PU.1 and GATA-3
Abstract
PU.1 and GATA-3 are transcription factors that are required for development of T cell progenitors from the earliest stages. Neither one is a simple positive regulator for T lineage specification, however. When expressed at elevated levels at early stages of T cell development, each of these transcription factors blocks T cell development within a different, characteristic time window, with GATA-3 overexpression initially inhibiting at an earlier stage than PU.1. These perturbations are each associated with a distinct spectrum of changes in the regulation of genes needed for T cell development. Both transcription factors can interfere with expression of the Rag-1 and Rag-2 recombinases, while GATA-3 notably blocks PU.1 and IL-7Rα expression, and PU.1 reduces expression of HES-1 and c-Myb. A first-draft assembly of the regulatory targets of these two factors is presented as a provisional gene network. The target genes identified here provide insight into the basis of the effects of GATA-3 or PU.1 overexpression and into the regulatory changes that distinguish the developmental time windows for these effects.
Additional Information
© 2002 Elsevier Science (USA) Received 28 January 2002, Revised 27 March 2002, Accepted 28 March 2002, Available online 25 May 2002. We thank Hergen Spits (Netherlands Cancer Institute), Garry Nolan (Stanford University), and David Rawlings (UCLA) for the pLZRS vector, and Schickwann Tsai (University of Washington) for the BHK-MKL cells. We greatly appreciate the insightful comments and valuable criticism provided by Jonathan Rast and Eric Davidson (Caltech) at several points throughout this work. We also thank Shirley Pease, Bruce Kennedy, and Eva Borucka of the Caltech Transgenic Animal Facility for timed matings; Rochelle Diamond and Pat Koen of the Flow Cytometry/Cell Sorting Facility for fluorescence-activated cell sorting; Dr. Suzanna Horvath and members of the Caltech Biopolymer Synthesis facility for oligonucleotide synthesis; and the Caltech DNA sequencing facility for sequencing. We also gratefully acknowledge the contributions of Elizabeth-Sharon D. David, Rochelle Diamond, Janice C. Telfer, Hua Wang, Angela Weiss, and Mary A. Yui within the lab, for RNA samples, helpful discussions, and permission to cite unpublished results. The work was initiated with funding from the Stowers Institute for Medical Research and supported afterwards by grants to E.V.R. from the NIH (CA90233) and NSF (MCB-9983129).Additional details
- Eprint ID
- 74092
- Resolver ID
- CaltechAUTHORS:20170206-140435747
- CA90233
- NIH
- MCB-9983129
- NSF
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2017-02-06Created from EPrint's datestamp field
- Updated
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2021-11-11Created from EPrint's last_modified field