This proposal addresses the question of how pluripotent hematopoietic precursors undergo specification and commitment to the T- lymphocyte lineage. In the past two years, the investigator's group has systematically identified molecular landmarks for this process, that is, specific changes in expression of multiple T-cell and non-T-cell (B-cell or dendritic-cell) genes that are correlated with each developmental transition. The investigator has also correlated these changes in target gene expression with parallel changes in the pattern of expression of particular members of the Ets, bHLH, and CBFa transcription factor families. The investigator has thus identified a discrete set of candidates for factors that might participate in the direct changes of phenotype of differentiating T-cell precursors and/or in the focusing of their developmental potential. Of particular interest is the Ets family transcription factor PU. l, which appears to be shut off abruptly at the stage when precursors become irreversibly committed to the T lineage. Most recently, the investigator has found that forced expression of PU. 1 in T-cell precursors both restricts entry into the T-cell differentiation pathway and blocks progression through the later, critical beta-selection checkpoint of the few cells that do enter this pathway. The goal of this project is to define the underlying mechanisms of T-lineage specification, using as probes the gene expression landmarks the investigator has defined and the ability of PU. 1 overexpression to perturb these mechanisms. The investigator plans: (1). To determine the structural and temporal requirements for PU. 1 inhibition of lymphoid development; ( 2). To establish direct linkages between expression of particular genes by precursor cells and the abilities of those cells to give rise to T, B, NK, dendritic, or mast cells; (3) To test the roles of developmentally regulated transcription factors in the alteration of expression of these indicator genes, and of PU.1 itself.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA090233-02
Application #
6498017
Study Section
Hematology Subcommittee 2 (HEM)
Program Officer
Mufson, R Allan
Project Start
2001-01-12
Project End
2005-12-31
Budget Start
2002-01-12
Budget End
2002-12-31
Support Year
2
Fiscal Year
2002
Total Cost
$346,579
Indirect Cost
Name
California Institute of Technology
Department
Type
Schools of Arts and Sciences
DUNS #
078731668
City
Pasadena
State
CA
Country
United States
Zip Code
91125
Longabaugh, William J R; Zeng, Weihua; Zhang, Jingli A et al. (2017) Bcl11b and combinatorial resolution of cell fate in the T-cell gene regulatory network. Proc Natl Acad Sci U S A 114:5800-5807
Kueh, Hao Yuan; Yui, Mary A; Ng, Kenneth K H et al. (2016) Asynchronous combinatorial action of four regulatory factors activates Bcl11b for T cell commitment. Nat Immunol 17:956-65
Rothenberg, Ellen V; Kueh, Hao Yuan; Yui, Mary A et al. (2016) Hematopoiesis and T-cell specification as a model developmental system. Immunol Rev 271:72-97
Rothenberg, Ellen V (2016) Eric Davidson: Steps to a gene regulatory network for development. Dev Biol 412:S7-19
Rothenberg, Ellen V (2015) Immune Cell Identity: Perspective from a Palimpsest. Perspect Biol Med 58:205-28
Champhekar, Ameya; Damle, Sagar S; Freedman, George et al. (2015) Regulation of early T-lineage gene expression and developmental progression by the progenitor cell transcription factor PU.1. Genes Dev 29:832-48
Scripture-Adams, Deirdre D; Damle, Sagar S; Li, Long et al. (2014) GATA-3 dose-dependent checkpoints in early T cell commitment. J Immunol 193:3470-91
Rothenberg, Ellen V (2014) The chromatin landscape and transcription factors in T cell programming. Trends Immunol 35:195-204
Rothenberg, Ellen V (2014) Transcriptional control of early T and B cell developmental choices. Annu Rev Immunol 32:283-321
Rothenberg, Ellen V; Champhekar, Ameya; Damle, Sagar et al. (2013) Transcriptional establishment of cell-type identity: dynamics and causal mechanisms of T-cell lineage commitment. Cold Spring Harb Symp Quant Biol 78:31-41

Showing the most recent 10 out of 43 publications