3D‐Epigenomic Regulation of Gene Transcription in Hepatocellular Carcinoma

The fundamental cause of transcription dysregulation in hepatocellular carcinoma (HCC) remains elusive. To investigate the underlying mechanisms, comprehensive 3D‐epigenomic analyses are performed in cellular models of THLE2 (a normal hepatocytes cell line) and HepG2 (a hepatocellular carcinoma cell line) using integrative approaches for chromatin topology, genomic and epigenomic variation, and transcriptional output. Comparing the 3D‐epigenomes in THLE2 and HepG2 reveal that most HCC‐associated genes are organized in complex chromatin interactions mediated by RNA polymerase II (RNAPII). Incorporation of genome‐wide association studies (GWAS) data enables the identification of non‐coding genetic variants that are enriched in distal enhancers connecting to the promoters of HCC‐associated genes via long‐range chromatin interactions, highlighting their functional roles. Interestingly, CTCF binding and looping proximal to HCC‐associated genes appear to form chromatin architectures that overarch RNAPII‐mediated chromatin interactions. It is further demonstrated that epigenetic variants by DNA hypomethylation at a subset of CTCF motifs proximal to HCC‐associated genes can modify chromatin topological configuration, which in turn alter RNAPII‐mediated chromatin interactions and lead to dysregulation of transcription. Together, the 3D‐epigenomic analyses provide novel insights of multifaceted interplays involving genetics, epigenetics, and chromatin topology in HCC cells.