T-bet employs diverse regulatory mechanisms to repress transcription

Abstract

Lineage-defining transcription factors are responsible for activating the signature genes required for a given cell fate. They are also needed to repress the genetic programs associated with alternative lineage decisions. The T-box transcription factor T-bet is required for CD4(+) T helper 1 (Th1) cell differentiation. Numerous studies have explored the mechanisms by which T-bet activates the Th1 gene profile, but until recently not much was known about the mechanisms that T-bet utilizes to negatively regulate alternative T helper cell differentiation pathways such as the Th2 and Th17 fates. Here, we discuss new advances in the field that highlight the diverse mechanisms that T-bet employs to antagonize the gene programs for alternative T helper cell fates.

Figure 1. Models representing the mechanisms by which T-bet positively and negatively regulates gene expression

(A) T-bet directly activates the Th1-signature gene program. T-bet induces transcription by recruiting chromatin remodeling complexes (including the histone H3K4-methyltransferase, Set7/9, as well as the histone H3K27-demethlyase, Jmjd3) to its target genes. (B) T-bet indirectly represses alternative T helper cell genetic programs. In scenario (I), T-bet physically associates with the Th2-lineage-defining transcription factor GATA3 to prevent it from binding to and directly activating Th2-signature genes. In the second scenario (II), T-bet physically interacts with Runx1, which prevents Runx1 from activating Rorc (the gene that encodes the Th17-lineage-defining transcription factor Rorγt). (C) T-bet can directly repress gene transcription by two mechanisms. In the first mechanism (I), T-bet directly recruits the transcriptional repressor, Bcl-6, to repress the promoter activity of genes preferentially expressed in alternative T helper cell subtypes. In the second mechanism (II), T-bet binding to a promoter prevents a required activator (activator X: Act. X) from recognizing its DNA binding element because there is a partial overlap between the T-bet and Act. X binding sites (represented by the multicolored DNA-binding element). Thus, T-bet DNA-binding to the promoter displaces a required activator to prevent gene transcription. It is possible that the T-bet-dependent repression of Pdcd1 may represent an example of this mechanism.