Id1 induces apoptosis through inhibition of RORgammat expression

Basic 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.

We designed a unique strategy to search for genes directly controlled by E proteins and found RORgammat to be a top candidate. Using microarray analyses and reverse-transcriptase PCR assays, we showed that Id1 expression diminished RORgammat mRNA levels in T cell lines and primary thymocytes while induction of E protein activity restored RORgammat expression. E proteins were found to specifically bind to the promoter region of RORgammat, suggesting their role in activating transcription of the gene. Functional significance of E protein-controlled RORgammat expression was established based on the finding that RORgammat rescued apoptosis caused by Id1 overexpression. Furthermore, expression of RORgammat prevented Id1-induced p38 MAP kinase hyper-activation.

These results suggest that E protein-dependent RORgammat gene expression aids the survival of developing thymocytes, which provides a possible explanation for the massive apoptosis found in Id1 transgenic mice.