Remarkably, our analysis of whole genome bisulfite DNA sequencing revealed that the differential CTCF binding and extended looping associated with HCC‐specific genes in normal hepatocytes and HCC cells are highly correlated with epigenetyic states of 5mC methylation or demethylation, suggesting a robust imprinting and reprogramming mechanism involved in regulating the dynamics of DNA methylation/demethylation that in turn alter chromatin folding architecture and control transcription of HCC‐associated genes during the transformation from normal hepatocytes to HCC cells. This evidence concerns the gene CTCF and hepatocellular carcinoma.