Accessibility control of TCR Vγ region by STAT5

Abstract

The signal of the IL-7R and signal transducers and activators of transcription (STAT) 5 plays an essential role in gammadelta T-cell development by inducing V-J recombination in the TCRgamma locus. Previously, we have shown that STAT5 binds to the Jgamma promoters and controls chromatin accessibility by histone acetylation. However, little is known on control mechanism of Vgamma region by the IL-7R. To elucidate the regulation by STAT5, we first analyzed the chromatin status of Vgamma region in primary thymocytes. The levels of histone H3 acetylation are high at Vgamma5, HsA element and Vgamma2 in Rag2(-/-) thymocytes but low in IL-7R alpha-chain (IL-7Ralpha)-deficient early thymocytes, suggesting that IL-7R signaling controls the accessibility of the Vgamma region. In addition, high levels of histone H3 acetylation and germ line transcription were induced at Vgamma5 and HsA by cytokine and STAT5 in cytokine-dependent Ba/F3 and other hematopoietic cell lines. Importantly, the chromatin accessibility of Vgamma5 gene is increased by cytokine signal. Furthermore, STAT5 was not recruited to a non-canonical STAT-binding motif in the endogenous chromatin of the Vgamma5 promoter by cytokine stimulation, while STAT5 binds to a consensus motif in the HsA element. In accordance with this result, STAT5 does not directly activate the Vgamma5 promoter by reporter assay. These results suggested that while STAT5 directly binds to HsA element and induces its histone acetylation, STAT5 indirectly activates the Vgamma5 promoter. Thus, this study implies a potential role of STAT5 in accessibility control of Vgamma region, especially at Vgamma5 and HsA.