Deciphering TP53- and SRF-mediated regulatory features of three-dimensional chromatin structure in cancer-associated fibroblasts from liver cancer Ppatients using HiChIP sequencing
Aberrant activation of cancer-associated fibroblasts is a key driver of proliferation, invasion, and microenvironment remodeling in liver cancer. Transcription factor-mediated three-dimensional chromatin remodeling precisely regulates the specific expression of target genes, and plays a central role in the imbalance of tumor microenvironment homeostasis and the malignant progression of tumors. To explore the molecular mechanism of spatial chromatin regulation in the liver cancer microenvironment, this study took cancer-associated fibroblasts derived from liver cancer patients as research subjects, and applied high-throughput HiChIP sequencing to systematically analyze the genome-wide binding distribution of the tumor suppressor transcription factor TP53 and the oncogenic transcription factor SRF, as well as the three-dimensional chromatin loop structures mediated by the two factors. We comprehensively identified long-range chromatin interaction sites regulated by the two transcription factors, screened differential chromatin interaction regions and core regulatory target genes, and compared the distribution patterns and functional differences of three-dimensional genome structures controlled by TP53 and SRF. By integrating gene functional enrichment analysis and transcriptional regulatory network analysis, we further clarified the molecular mechanism by which the two transcription factors modulate biological processes including liver cancer microenvironment remodeling, cell proliferation, invasion and metastasis through reshaping chromatin spatial conformation.