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-7Ralpha 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.

Differential expression of notch signaling-related transcripts accompanies Pro-thymocyte proliferation and phenotype transition induced by epidermal growth factor plus insulin in fetal thymus organ cultures

“…Transcripts for gene regulators such as GATA 3, that here was not correlated with cellular proliferation as was reported in literature (Hattori et al 1996b, Hendriks et al 1999, for TCF1a (Hattori et al 1996b), PU.1 (Anderson et al 2002), c-MYB (Rothenberg 2002), c-MYC (Douglas et al 2001), SCL and HEB (Herblot et al 2000), E47 (E2A) and its inhibitor Id2 (Anderson et al 2002), as for the Tcell receptor gene-rearranging enzymes RAG-1 and RAG-2, were seen in both conditions (Fig. 2A).…”

GATA3 Abundance Is a Critical Determinant of T Cell Receptor β Allelic Exclusion

“…Proplatelet formation is inhibited after either diminished or excessive expression of the transcription factor MafG in megakaryocytes (67), and T cell development in the thymus is blocked when there is either too little or too much GATA3 (32,33,40,68,69). Of note in this regard, the inactivation of one Gata3 allele often results in a mild reduction in T cell development in humans (HDR [hypoparathyroidism, deafness, and renal dysplasia] syndrome) (70)(71)(72) and in mice (49), while a 2-fold increase in the GATA3 protein abundance has been shown to induce T cell lymphoma (73).…”

LymphTF-DB: a database of transcription factors involved in lymphocyte development

“…The goal of this work is to organize these interactions in a logical manner that can be easily accessed by immunologists studying lymphocyte development and developmental biologists exploring transcriptional regulatory networks (TRN). [15][16][17][18] Results and discussion Review of relevant literature has resulted in the collection and cataloging of 111 unique transcription factors involved or implicated in B-or T-cell development at the time of publication. This number represents 55 factors for which interactions with a specific target gene have been shown, and an additional 56 factors that have been shown to be present or transcriptionally active during Band T-cell development.…”