Abstract

BackgroundBasic helix-loop-helix E proteins are transcription factors that play crucial roles in T cell development by controlling thymocyte proliferation, differentiation and survival. E protein functions can be repressed by their naturally occurring inhibitors, Id proteins (Id1-4). Transgenic expression of Id1 blocks T cell development and causes massive apoptosis of developing thymocytes. However, the underlying mechanisms are not entirely understood due to relatively little knowledge of the target genes regulated by E proteins.ResultsWe designed a unique strategy to search for genes directly controlled by E proteins and found RORγt to be a top candidate. Using microarray analyses and reverse-transcriptase PCR assays, we showed that Id1 expression diminished RORγt mRNA levels in T cell lines and primary thymocytes while induction of E protein activity restored RORγt expression. E proteins were found to specifically bind to the promoter region of RORγt, suggesting their role in activating transcription of the gene. Functional significance of E protein-controlled RORγt expression was established based on the finding that RORγt rescued apoptosis caused by Id1 overexpression. Furthermore, expression of RORγt prevented Id1-induced p38 MAP kinase hyper-activation.ConclusionThese results suggest that E protein-dependent RORγt gene expression aids the survival of developing thymocytes, which provides a possible explanation for the massive apoptosis found in Id1 transgenic mice.

Highlights

  • Basic helix-loop-helix E proteins are transcription factors that play crucial roles in T cell development by controlling thymocyte proliferation, differentiation and survival

  • These results provide a possible explanation for the massive apoptosis occurring in double positive (DP) thymocytes in Id1 transgenic mice, namely, reduced RORγt expression and diminished thymocyte survival due to inhibition of E protein function

  • Alterations in gene expression by loss or gain of E protein function To understand the molecular mechanisms by which E proteins control T cell development, we sought for genes whose expression is directly regulated by E2A transcription factors using DNA microarray analyses

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Summary

Introduction

Basic helix-loop-helix E proteins are transcription factors that play crucial roles in T cell development by controlling thymocyte proliferation, differentiation and survival. T lymphocytes differentiate in the thymus from multipotent progenitors derived from the bone marrow. Elaborate selection schemes ensure each developing thymocyte expresses a functional T cell receptor with appropriate avidity to foreign peptides presented by self MHC while simultaneously maintaining tolerance to self-antigens [5,6]. These selection processes involve precise regulation of cell proliferation and apoptosis. Mechanisms are in place to ensure desirable mature thymocytes survive and exit the thymus

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