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STAG2 regulates interferon signaling in melanoma via enhancer loop reprogramming

Author

Listed:
  • Zhaowei Chu

    (Massachusetts General Hospital and Harvard Medical School
    The Second Hospital Affiliated to Xi’an Jiaotong University)

  • Lei Gu

    (Max Planck Institute for Heart and Lung Research)

  • Yeguang Hu

    (Massachusetts General Hospital and Harvard Medical School)

  • Xiaoyang Zhang

    (Fudan University)

  • Man Li

    (Massachusetts General Hospital and Harvard Medical School)

  • Jiajia Chen

    (Dana-Farber Cancer Institute
    Broad Institute of MIT and Harvard)

  • Da Teng

    (Massachusetts General Hospital and Harvard Medical School)

  • Man Huang

    (Harvard Medical School)

  • Che-Hung Shen

    (National Health Research Institutes)

  • Li Cai

    (University of Texas MD Anderson Cancer Center)

  • Toshimi Yoshida

    (Massachusetts General Hospital and Harvard Medical School)

  • Yifeng Qi

    (Massachusetts Institute of Technology)

  • Zhixin Niu

    (Max Planck Institute for Heart and Lung Research)

  • Austin Feng

    (Massachusetts General Hospital and Harvard Medical School)

  • Songmei Geng

    (The Second Hospital Affiliated to Xi’an Jiaotong University)

  • Dennie T. Frederick

    (Massachusetts General Hospital Cancer Center)

  • Emma Specht

    (Massachusetts General Hospital Cancer Center)

  • Adriano Piris

    (Brigham and Women’s Hospital and Harvard Medical School)

  • Ryan J. Sullivan

    (Massachusetts General Hospital Cancer Center)

  • Keith T. Flaherty

    (Massachusetts General Hospital Cancer Center)

  • Genevieve M. Boland

    (Massachusetts General Hospital)

  • Katia Georgopoulos

    (Massachusetts General Hospital and Harvard Medical School)

  • David Liu

    (Dana-Farber Cancer Institute
    Broad Institute of MIT and Harvard)

  • Yang Shi

    (Harvard Medical School
    Oxford University)

  • Bin Zheng

    (Massachusetts General Hospital and Harvard Medical School)

Abstract

The cohesin complex participates in the organization of 3D genome through generating and maintaining DNA loops. Stromal antigen 2 (STAG2), a core subunit of the cohesin complex, is frequently mutated in various cancers. However, the impact of STAG2 inactivation on 3D genome organization, especially the long-range enhancer-promoter contacts and subsequent gene expression control in cancer, remains poorly understood. Here we show that depletion of STAG2 in melanoma cells leads to expansion of topologically associating domains (TADs) and enhances the formation of acetylated histone H3 lysine 27 (H3K27ac)-associated DNA loops at sites where binding of STAG2 is switched to its paralog STAG1. We further identify Interferon Regulatory Factor 9 (IRF9) as a major direct target of STAG2 in melanoma cells via integrated RNA-seq, STAG2 ChIP-seq and H3K27ac HiChIP analyses. We demonstrate that loss of STAG2 activates IRF9 through modulating the 3D genome organization, which in turn enhances type I interferon signaling and increases the expression of PD-L1. Our findings not only establish a previously unknown role of the STAG2 to STAG1 switch in 3D genome organization, but also reveal a functional link between STAG2 and interferon signaling in cancer cells, which may enhance the immune evasion potential in STAG2-mutant cancer.

Suggested Citation

  • Zhaowei Chu & Lei Gu & Yeguang Hu & Xiaoyang Zhang & Man Li & Jiajia Chen & Da Teng & Man Huang & Che-Hung Shen & Li Cai & Toshimi Yoshida & Yifeng Qi & Zhixin Niu & Austin Feng & Songmei Geng & Denni, 2022. "STAG2 regulates interferon signaling in melanoma via enhancer loop reprogramming," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-29541-9
    DOI: 10.1038/s41467-022-29541-9
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    References listed on IDEAS

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    1. Wibke Schwarzer & Nezar Abdennur & Anton Goloborodko & Aleksandra Pekowska & Geoffrey Fudenberg & Yann Loe-Mie & Nuno A Fonseca & Wolfgang Huber & Christian H. Haering & Leonid Mirny & Francois Spitz, 2017. "Two independent modes of chromatin organization revealed by cohesin removal," Nature, Nature, vol. 551(7678), pages 51-56, November.
    2. Emily Crane & Qian Bian & Rachel Patton McCord & Bryan R. Lajoie & Bayly S. Wheeler & Edward J. Ralston & Satoru Uzawa & Job Dekker & Barbara J. Meyer, 2015. "Condensin-driven remodelling of X chromosome topology during dosage compensation," Nature, Nature, vol. 523(7559), pages 240-244, July.
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