| Description |
Transposable elements (TEs) contribute to gene expression regulation by acting as cis-regulatory elements that attract transcription factors and epigenetic regulators. This research aimed to explore the functional and clinical implications of transposable element-related molecular events in hepatocellular carcinoma (HCC), focusing on the mechanism through which liver-specific accessible TEs (liver-TEs) regulate adjacent gene expression. Through extensive epigenomic and transcriptomic analyses, coupled with CRISPR/Cas9-mediated genomic editing, we explored the impact of liver-TEs on transcriptional regulation. Our findings revealed that the expression of HNF4A is inversely regulated by proximate liver-TEs, which facilitates HCC cell proliferation. From a mechanistic perspective, 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. Additionally, KDM1A interacts and colocalizes with HNF4A in the genome, leading to transcriptional inhibition of HNF4A target genes. The suppression of HNF4A mediated by KDM1A promotes HCC cell proliferation. Moreover, the DNA-binding protein ZMYM3 emerges as a critical mediator facilitating the recruitment of KDM1A by liver-TEs. Remarkably, our study establishes a clinical relevance, as elevated expression of KDM1A correlates with poor prognosis in HCC patients, and targeting KDM1A can effectively inhibit HCC cell growth. In conclusion, this study uncovers a liver- TE/KDM1A/HNF4A regulatory axis that promotes HCC growth and highlights the potential of targeting KDM1A for HCC therapy. Our findings provide insight into the transposable element-related molecular mechanisms underlying HCC progression. |
