Runx-mediated regulation of CCL5 via antagonizing two enhancers influences immune cell function and anti-tumor immunity

Wooseok Seo, Kanako Shimizu, Satoshi Kojo, Arinze Okeke, Terumi Kohwi-Shigematsu, Shin ichiro Fujii, Ichiro Taniuchi

研究成果: Contribution to journalArticle査読

6 被引用数 (Scopus)

抄録

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.

本文言語英語
論文番号1562
ジャーナルNature communications
11
1
DOI
出版ステータス出版済み - 12 1 2020
外部発表はい

All Science Journal Classification (ASJC) codes

  • 化学 (全般)
  • 生化学、遺伝学、分子生物学(全般)
  • 物理学および天文学(全般)

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