Development is a vectorial process that is necessarily under the control of multiple genes and their regulatory interactions. The handful of developmental genetic regulatory networks that have been deciphered to date reveal embryonic development to involve large, multi-layered networks, nonlinear regulatory processes, and complex dynamics mediated by multiple feedforward, lateral, and feedback interactions. Because of these characteristics, development can only be properly understood within the framework of systems biology. A particularly important model to understand is blood cell development. All blood cells are generated continuously throughout life from hematopoietic stem cells (HSC), via tightly regulated developmental processes that are disrupted in a number of major blood diseases. Developing precursors of each of the diverse blood cell types are defined not only by their acquisition of mature characteristics but also by the degree of access they retain to alternative blood-cell differentiation pathways. T lymphocyte differentiation from HSC is a system that offers unusually clear access to the time course of a developmental choice and the intermediate stages through which it passes. T-lineage fate selection is based on a protracted competition among regulatory inputs, which precursor cells only resolve after many cell cycles. This project will use computational and experimental studies of T-cell development to decipher how environmental and intrinsic regulatory inputs are integrated to drive mammalian blood stem cells to choose among different leukocyte developmental fates, and to make the transition from plasticity to commitment. Hamid Bolouri will lead the computational component of the project. His group will develop computational methods for prediction and integration of protein-protein and protein-DNA interactions with gene perturbation data to generate a series of alternative gene-network hypotheses. His group will use formal statistical model selection to refine kinetic models of network operation. These computational predictions will guide the experimental program and interpret the data it generates. Ellen Rothenberg will lead the experimental component of the project. The Rothenberg group will use in vitro differentiation systems, gene-specific perturbations, and quantitative multigene expression data to dissect regulatory network relationships that guide T-cell emergence from stem cells. The kinetics of this process will also be tracked for individual cells. Specific hypotheses tested in the perturbations will be refined iteratively through ongoing interaction with the modeling studies done by the Bolouri group. Blood cells are generated from stem cells throughout life, and many human diseases trace their origin to a derangement in the complex regulation of blood-cell developmental processes. T-cell development has many features that make it an excellent system in which to study the mechanisms that control cell fate choice and the rigorous regulatory mechanisms that guide immature cells away from abnormal fates. Through a dialogue between computational modeling and experimental analysis, we will explain the regulatory network that makes T-cell development robust, providing new insights into mechanisms that can prevent disease. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Exploratory/Developmental Grants Phase II (R33)
Project #
5R33HL089123-02
Application #
7487778
Study Section
Special Emphasis Panel (ZHL1-CSR-K (M1))
Program Officer
Qasba, Pankaj
Project Start
2007-08-22
Project End
2010-06-30
Budget Start
2008-07-01
Budget End
2009-06-30
Support Year
2
Fiscal Year
2008
Total Cost
$486,091
Indirect Cost
Name
California Institute of Technology
Department
Type
Schools of Arts and Sciences
DUNS #
009584210
City
Pasadena
State
CA
Country
United States
Zip Code
91125
Rothenberg, Ellen V (2017) Fitting structure to function in gene regulatory networks. Hist Philos Life Sci 39:37
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 (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
Rothenberg, Ellen V (2014) Transcriptional control of early T and B cell developmental choices. Annu Rev Immunol 32:283-321
Li, Long; Zhang, Jingli A; Dose, Marei et al. (2013) A far downstream enhancer for murine Bcl11b controls its T-cell specific expression. Blood 122:902-11
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
Rothenberg, Ellen V (2013) Epigenetic mechanisms and developmental choice hierarchies in T-lymphocyte development. Brief Funct Genomics 12:512-24
Kueh, Hao Yuan; Champhekar, Ameya; Champhekhar, Ameya et al. (2013) Positive feedback between PU.1 and the cell cycle controls myeloid differentiation. Science 341:670-3
Zhang, Jingli A; Mortazavi, Ali; Williams, Brian A et al. (2012) Dynamic transformations of genome-wide epigenetic marking and transcriptional control establish T cell identity. Cell 149:467-82

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