Interaction of Ets-1 with HDAC1 Represses IL-10 Expression in Th1 Cells

Abstract

IL-10 is a multifunctional cytokine that plays a crucial role in immunity and tolerance. IL-10 is produced by diverse immune cell types, including B cells and subsets of T cells. Although Th1 produce IL-10, their expression levels are much lower than Th2 cells under conventional stimulation conditions. The potential role of E26 transformation-specific 1 (Ets-1) transcription factor as a negative regulator for Il10 gene expression in CD4+ T cells has been implicated previously. In this study, we investigated the underlying mechanism of Ets-1–mediated Il10 gene repression in Th1 cells. Compared with wild type Th1 cells, Ets-1 knockout Th1 cells expressed a significantly higher level of IL-10, which is comparable with that of wild type Th2 cells. Upregulation of IL-10 expression in Ets-1 knockout Th1 cells was accompanied by enhanced chromatin accessibility and increased recruitment of histone H3 acetylation at the Il10 regulatory regions. Reciprocally, Ets-1 deficiency significantly decreased histone deacetylase 1 (HDAC1) enrichment at the Il10 regulatory regions. Treatment with trichostatin A, an inhibitor of HDAC family, significantly increased Il10 gene expression by increasing histone H3 acetylation recruitment. We further demonstrated a physical interaction between Ets-1 and HDAC1. Coexpression of Ets-1 with HDAC1 synergistically repressed IL-10 transcription activity. In summary, our data suggest that an interaction of Ets-1 with HDAC1 represses the Il10 gene expression in Th1 cells.

The Proto-oncogene Transcription Factor Ets1 Regulates Neural Crest Development through Histone Deacetylase 1 to Mediate Output of Bone Morphogenetic Protein Signaling

“…Promoter-A previous study has reported that Ets1 interacts with HDAC1 to repress target genes in Th1 cells (52). To explore the possibility that Ets1 represses BMP target genes through epigenetic control during NC development, we first assessed the interaction between Ets1 and HDAC1 in both Xenopus embryos and cultured mammalian cells.…”

Characterization of the 5′-flanking region of the mouse asparagine-linked glycosylation 12 homolog gene

“…However, it is unclear if and which transcription factors might form a heterocomplex to bind the ALG12 promoter because the Sp1 and Ets families consist of various members [16,19,20,27]. Moreover, YY1 and some members of the Sp1 and Ets families have been reported to interact with the HDAC family of co-factors to regulate gene expression [18,24,29,30]. YY1 has also been reported to behave like a scaffold for several transcription-related factors that are recruited to and assembled at the promoter region without directly binding to the consensus sequence for YY1 [18,25].…”

Cellular Repressor of E1A-Stimulated Genes Is a Critical Determinant of Vascular Remodeling in Response to Angiotensin II

“…Moreover, this notion was confirmed by siRNA-mediated silencing of Ets1, which led to inhibition of Ang II-induced downregulation of CREG Ets1 has a dual function, acting as both a transcriptional activator and a repressor via association with specific cofactors and in combination with other TFs, depending on promoter context. 28 In most cases, Ets1 positively regulates the expression of its target genes. However, Ets1 also functions as repressor of its target genes, [28][29][30] including interleukin-10, cyclin D3, retinoblastoma-associated factor 600, AXL receptor tyrosine kinase, MET tyrosine kinase, β-2-adrenergic receptor, stromal cell-derived factor receptor 1, ATP5G3, 5-tubulin, serine-threonine-kinase 6, and anilin/actin-binding protein.…”

“…28 In most cases, Ets1 positively regulates the expression of its target genes. However, Ets1 also functions as repressor of its target genes, [28][29][30] including interleukin-10, cyclin D3, retinoblastoma-associated factor 600, AXL receptor tyrosine kinase, MET tyrosine kinase, β-2-adrenergic receptor, stromal cell-derived factor receptor 1, ATP5G3, 5-tubulin, serine-threonine-kinase 6, and anilin/actin-binding protein. In addition, Ets1 can also suppress gene expression through interacting with repressive factors like EAP1/Daxx, HDAC1, mSin3a, and DNA methyltransferase 3a and 3b.…”