STAG2 regulates interferon signaling in melanoma via enhancer loop reprogramming

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, Dennie T. Frederick, Emma Specht, Adriano Piris, Ryan J. Sullivan, Keith T. Flaherty, Genevieve M. Boland, Katia Georgopoulos, David Liu, Yang Shi and Bin Zheng ()
Additional contact information
Zhaowei Chu: Massachusetts General Hospital and Harvard Medical School
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
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
Yang Shi: Harvard Medical School
Bin Zheng: Massachusetts General Hospital and Harvard Medical School

Nature Communications, 2022, vol. 13, issue 1, 1-11

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-29541-9

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