Runx-mediated regulation of CCL5 via antagonizing two enhancers influences immune cell function and anti-tumor immunity
Year: 2020
Type: article
Abstract: CCL5 is a unique chemokine with distinct stage and cell-type specificities for regulating inflammation, but how these specificities are achieved and how CCL5 modulates immune responses is not well understood. Here we identify two stage-specific enhancers: the proximal enhancer mediates the constitutive CCL5 expression during the steady state, while the distal enhancer located 1.35 Mb from the promoter induces CCL5 expression in activated cells. Both enhancers are antagonized by RUNX/CBFβ complexes, and SATB1 further mediates the long-distance interaction of the distal enhancer with the promoter. Deletion of the proximal enhancer decreases CCL5 expression and augments the cytotoxic activity of tissue-resident T and NK cells, which coincides with reduced melanoma metastasis in mouse models. By contrast, increased CCL5 expression resulting from RUNX3 mutation is associated with more tumor metastasis in the lung. Collectively, our results suggest that RUNX3-mediated CCL5 repression is critical for modulating anti-tumor immunity.
Source: Nature Communications
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $5,380
Awards: Analyses of transcription factors networks that govern T lymphocyte development, Novel regulatory mechanisms of gene expression via Runx-dependent gene silencer, G7688520727, Understanding mechanisms that regulate Runx complex function through C-terminus structures, G7770831241, Regulatory mechanisms controlling CCL5 chemokine to maintain tissue homeostasis, G8032836602, Runx-mediated regulation of chemokine CCL5 for lung diseases, G851079297
OpenAlex ID: W3013135919