A gene regulatory network armature for T lymphocyte specification

Proc Natl Acad Sci U S A. 2008 Dec 23;105(51):20100-5. doi: 10.1073/pnas.0806501105. Epub 2008 Dec 22.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • GATA3 Transcription Factor / genetics*
  • Gene Expression Regulation
  • Gene Regulatory Networks*
  • Hematopoietic Stem Cells / cytology
  • Lymphopoiesis / genetics*
  • Mice
  • Proto-Oncogene Proteins / genetics*
  • Receptors, Notch
  • T-Lymphocytes / cytology*
  • Trans-Activators / genetics*
  • Transcription Factors

Substances

  • GATA3 Transcription Factor
  • Proto-Oncogene Proteins
  • Receptors, Notch
  • Trans-Activators
  • Transcription Factors
  • proto-oncogene protein Spi-1