A gene regulatory network armature for T lymphocyte specification.
Choice of a T lymphoid fate by hematopoietic progenitor cells depends on sustained Notch-Delta signaling combined with tightly regulated activities of multiple transcription factors. To dissect the regulatory network connections that mediate this process, we have used high-resolution analysis of regulatory gene expression trajectories from the beginning to the end of specification, tests of the short-term Notch dependence of these gene expression changes, and analyses of the effects of overexpression of two essential transcription factors, namely PU.1 and GATA-3. Quantitative expression measurements of >50 transcription factor and marker genes have been used to derive the principal components of regulatory change through which T cell precursors progress from primitive multipotency to T lineage commitment. Our analyses reveal separate contributions of Notch signaling, GATA-3 activity, and down-regulation of PU.1. Using BioTapestry (www.BioTapestry.org), the results have been assembled into a draft gene regulatory network for the specification of T cell precursors and the choice of T as opposed to myeloid/dendritic or mast-cell fates. This network also accommodates effects of E proteins and mutual repression circuits of Gfi1 against Egr-2 and of TCF-1 against PU.1 as proposed elsewhere, but requires additional functions that remain unidentified. Distinctive features of this network structure include the intense dose dependence of GATA-3 effects, the gene-specific modulation of PU.1 activity based on Notch activity, the lack of direct opposition between PU.1 and GATA-3, and the need for a distinct, late-acting repressive function or functions to extinguish stem and progenitor-derived regulatory gene expression.
Georgescu
Constantin
C
Division of Biology 156-29, California Institute of Technology, Pasadena, CA 91125, USA.
Longabaugh
William J R
WJ
Scripture-Adams
Deirdre D
DD
David-Fung
Elizabeth-Sharon
ES
Yui
Mary A
MA
Zarnegar
Mark A
MA
Bolouri
Hamid
H
Rothenberg
Ellen V
EV
D000818:Animals; D050990:GATA3 Transcription Factor / Q000235:genetics*; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D006412:Hematopoietic Stem Cells / Q000166:cytology; D038041:Lymphopoiesis / Q000235:genetics*; D051379:Mice; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D051880:Receptors, Notch; D013601:T-Lymphocytes / Q000166:cytology*; D015534:Trans-Activators / Q000235:genetics*; D014157:Transcription Factors; D000099232:Proto-Oncogene Protein Spi-1
D050990:GATA3 Transcription Factor; D011518:Proto-Oncogene Proteins; D051880:Receptors, Notch; D015534:Trans-Activators; D014157:Transcription Factors; D000099232:Proto-Oncogene Protein Spi-1