Transposable elements-mediated recruitment of KDM1A epigenetically silences HNF4A expression to promote hepatocellular carcinoma

Tiantian Jing, Dianhui Wei, Xiaoli Xu, Chengsi Wu, Lili Yuan, Yiwen Huang, Yizhen Liu (), Yanyi Jiang () and Boshi Wang ()
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Tiantian Jing: Shanghai Jiao Tong University School of Medicine
Dianhui Wei: Shanghai Jiao Tong University School of Medicine
Xiaoli Xu: Shanghai Jiao Tong University School of Medicine
Chengsi Wu: Shanghai Jiao Tong University School of Medicine
Lili Yuan: Shanghai Jiao Tong University School of Medicine
Yiwen Huang: Shanghai Jiao Tong University School of Medicine
Yizhen Liu: Fudan University
Yanyi Jiang: Chinese Academy of Sciences
Boshi Wang: Shanghai Jiao Tong University School of Medicine

Nature Communications, 2024, vol. 15, issue 1, 1-21

Abstract: Abstract Transposable elements (TEs) contribute to gene expression regulation by acting as cis-regulatory elements that attract transcription factors and epigenetic regulators. This research aims to explore the functional and clinical implications of transposable element-related molecular events in hepatocellular carcinoma, focusing on the mechanism through which liver-specific accessible TEs (liver-TEs) regulate adjacent gene expression. Our findings reveal that the expression of HNF4A is inversely regulated by proximate liver-TEs, which facilitates liver cancer cell proliferation. Mechanistically, liver-TEs are predominantly occupied by the histone demethylase, KDM1A. KDM1A negatively influences the methylation of histone H3 Lys4 (H3K4) of liver-TEs, resulting in the epigenetic silencing of HNF4A expression. The suppression of HNF4A mediated by KDM1A promotes liver cancer cell proliferation. In conclusion, this study uncovers a liver-TE/KDM1A/HNF4A regulatory axis that promotes liver cancer growth and highlights KDM1A as a promising therapeutic target. Our findings provide insight into the transposable element-related molecular mechanisms underlying liver cancer progression.

Date: 2024
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DOI: 10.1038/s41467-024-49926-2

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