Chromatin looping-based CRISPR screen identifies TLK2 as chromatin loop formation regulator in cancer stemness plasticity

Zifeng Wang (), Fang Liu, Nana Chen, Jingjing Wu, Xinhao Li, Mouxiang Fang, Min Yan, Ji Zhang, Bing Deng, Lulu Wang, Xuan Wang, Meiling Liu, Deshun Zeng, Zhengzhi Zou, Bo Wang, Zhou Songyang, Bin He () and Quentin Liu ()
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Zifeng Wang: Sun Yat-sen University Cancer Center, Psychobehavioral Cancer Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Guangdong Provincial Clinical Research Center for Cancer
Fang Liu: Sun Yat-sen University Cancer Center, Psychobehavioral Cancer Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Guangdong Provincial Clinical Research Center for Cancer
Nana Chen: Sun Yat-sen University Cancer Center, Psychobehavioral Cancer Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Guangdong Provincial Clinical Research Center for Cancer
Jingjing Wu: Sun Yat-sen University Cancer Center, Psychobehavioral Cancer Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Guangdong Provincial Clinical Research Center for Cancer
Xinhao Li: Sun Yat-sen University Cancer Center, Psychobehavioral Cancer Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Guangdong Provincial Clinical Research Center for Cancer
Mouxiang Fang: South China Normal University
Min Yan: Sun Yat-sen University Cancer Center, Psychobehavioral Cancer Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Guangdong Provincial Clinical Research Center for Cancer
Ji Zhang: Sun Yat-sen University Cancer Center, Psychobehavioral Cancer Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Guangdong Provincial Clinical Research Center for Cancer
Bing Deng: Sun Yat-sen University Cancer Center, Psychobehavioral Cancer Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Guangdong Provincial Clinical Research Center for Cancer
Lulu Wang: Sun Yat-sen University Cancer Center, Psychobehavioral Cancer Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Guangdong Provincial Clinical Research Center for Cancer
Xuan Wang: Sun Yat-sen University Cancer Center, Psychobehavioral Cancer Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Guangdong Provincial Clinical Research Center for Cancer
Meiling Liu: Sun Yat-sen University Cancer Center, Psychobehavioral Cancer Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Guangdong Provincial Clinical Research Center for Cancer
Deshun Zeng: Sun Yat-sen University Cancer Center, Psychobehavioral Cancer Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Guangdong Provincial Clinical Research Center for Cancer
Zhengzhi Zou: South China Normal University
Bo Wang: Sun Yat-sen University Cancer Center, Psychobehavioral Cancer Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Guangdong Provincial Clinical Research Center for Cancer
Zhou Songyang: Sun Yat-sen University
Bin He: Sun Yat-sen University Cancer Center, Psychobehavioral Cancer Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Guangdong Provincial Clinical Research Center for Cancer
Quentin Liu: Sun Yat-sen University Cancer Center, Psychobehavioral Cancer Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Guangdong Provincial Clinical Research Center for Cancer

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract Targeting cancer cell plasticity through chromatin organization is an emerging research area, yet the molecular mechanisms that govern chromatin loop formation remain unclear. Here, we develop a CRISPR screen based on our engineered live-cell CTCF-cohesin contact reporters to identify regulators of chromatin loops. Our findings reveal that tousled-like kinase 2 (TLK2) functions as a key regulator of chromatin loop formation during the cancer stemness transition. Mechanistically, TLK2 phosphorylates DYNLL1, enhancing its interaction with CTCF to promote CTCF-cohesin hub formation at the KLF4 locus. Suppressing TLK2 impairs cancer stemness plasticity, sensitizes cancer cells to cytotoxic stress in vitro, and reduces lung metastases and enhances immunotherapy response in breast cancer mouse models. Clinically, elevated TLK2 expression correlates with poor prognosis in breast cancer patients. Collectively, these findings identify TLK2 as a potential therapeutic target for mitigating cancer stemness plasticity, highlighting chromatin loop-targeting therapy as a promising strategy to eradicate cancer stem cells.

Date: 2025
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DOI: 10.1038/s41467-025-64066-x

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