Activation of the mouse TCR enhancers by STAT5

Abstract

The IL-7R controls local accessibility of joining (J) gamma gene segments in the mouse TCRgamma locus by recruiting signal transducers and activators of transcription (STAT) 5 and transcriptional coactivators to the Jgamma germ line promoters and inducing histone acetylation and germ line transcription. Because STAT consensus motifs are conserved not only in the Jgamma promoters but also in the TCRgamma 3' enhancer (Egamma) elements, it is possible that STAT5 interacts with and activates Egamma. To address this question, we first showed that the lysine 4 residue of histone H3 is substantially methylated at Egamma1 and Egamma4 elements in wild-type early thymocytes and that the levels of the methylation are reduced in IL-7R alpha chain-deficient mice. We also showed that STAT5 has potential to elevate histone acetylation of the Egamma elements in a cytokine-dependent cell line by cytokine stimulation. Next, we demonstrated that STAT5 is recruited to the STAT consensus motifs in the Egamma elements after cytokine stimulation and that transcription factors Runt-related (Runx) and c-Myb are constitutively recruited to Egamma. Furthermore, we showed that STAT5 augments basal Egamma activity controlled by Runx and c-Myb. These results suggest that STAT5 is recruited to the consensus motifs in the Egamma elements by cytokine stimulation and augments basal Egamma activity independent of Runx and c-Myb. Therefore, this study implies that the Egamma elements might be activated in two successive steps, first by Runx and c-Myb and next by STAT5.