The higher expression levels of Eos in TReg cells than in effector T cells identified it as a potentially important transcription factor in TReg cell function. Previous studies have shown that Eos acts as a transcriptional repressor and that it associates with the co-repressor carboxy-terminal binding protein 1 (CTBP1), so the authors investigated whether Eos interacts with FOXP3 and acts as a transcriptional repressor in TReg cells. Indeed, Eos was shown to directly interact with FOXP3. FOXP3 suppresses the expression of interleukin-2 (Il2), as well as other genes, in TReg cells and the authors showed that the small interfering RNA (siRNA)-mediated knockdown of Eos abrogated this FOXP3-mediated suppression of IL-2 production. In addition, deletion of the Eos-binding site in FOXP3 reversed IL-2 suppression in TReg cells, indicating an essential role for Eos in FOXP3-mediated gene repression. Interestingly, knockdown of Eos affected only those genes that are suppressed by FOXP3; it did not affect FOXP3-induced genes.
Further analysis showed that Eos recruits CTBP1 to the Eos–FOXP3 complex and that this complex modulated the epigenetic status of the Il2 promoter. siRNA-mediated knockdown of Eos resulted in a significant increase in permissive histone 3 lysine 4 (H3K4) trimethylation and H3 and H4 acetylation levels in TReg cells. Furthermore, knockdown of either Eos or CTBP1 resulted in demethylation of genomic DNA at CpG dinucleotides in the Il2 promoter. These epigenetic modifications observed in the absence of functional Eos are similar to the epigenetic status of the Il2 promoter in effector T cells.
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