The regulation of TIM-3 transcription in T cells involves c-Jun binding but not CpG methylation at the TIM-3 promoter

Publication date: July 2016
Source:Molecular Immunology, Volume 75
Author(s): Su Jin Yun, Ka-Jung Jun, Kuniharu Komori, Mi Jin Lee, Myung-Hee Kwon, Yong-Joon Chwae, Kyongmin Kim, Ho-Joon Shin, Sun Park
Tim-3 is an immunomodulatory protein that is expressed constitutively on monocytes but is induced in activated T cells. The mechanisms involved in the regulation of TIM-3 transcription are poorly understood. In the present study, we investigated whether methylation of the TIM-3 promoter is involved in regulatingTIM-3 transcription in T cells, and identified a transcription factor that regulates TIM-3 transcription by associating with the TIM-3 minimal promoter region. Pyrosequencing of the TIM-3 promoter up to −1440bp revealed 11 hypermethylated CpG sites and 4 hypomethylated CpG sites in human CD4⁺ T cells as well as in CD11b⁺ cells. Dimethylation of histone H3 lysine 4 (H3K4), a mark of transcriptional activation, was predominantly found in the proximal TIM-3 promoter −954 to −34bp region, whereas trimethylation of H3K9 and H3K27, which are markers of transcriptional suppression, were mostly observed in the distal promoter −1549 to −1048bp region in human CD4⁺ T cells and CD11b⁺ cells. However, no change in the methylation status of CpG sites and the histone H3 in the TIM-3 promoter was found during induction of TIM-3 transcription in T cells. Finally, AP-1 involvement in TIM-3 transcription was shown in relation with the TIM-3 minimal promoter −146 to +144bp region. The present study defines the minimal TIM-3 promoter region and demonstrates its interaction with c-Jun during TIM-3 transcription in CD4⁺ T cells.



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