BACKGROUND Colorectal cancer (CRC) is the second most commonly diagnosed cancer in females and the third in males worldwide. Although existing evidence explained some critical functions of the single genetic abnormality in the pathogenesis of CRC, the function of interactors involved in the colon-specific regulatory network, especially DNA methylation regulated network is still poorly understood. MATERIAL AND METHODS In this work, matched gene expression and DNA methylation samples of CRC patients were retrieved. Differential gene expression and methylation analyses were performed. In addition, gene expression and DNA methylation were integrated into a colon-specific regulatory gene network, detecting the epigenetically regulated gene modules which drive CRC through an underlying epigenetic mechanism. Finally, the colon-specific DNA methylation-regulated gene modules were validated using an independent set of CRC patients. RESULTS Differential gene expression analysis demonstrated the upregulation of the cell cycle and DNA replication and downregulation of cGMP-PKG signaling pathway and calcium signaling pathway in CRC. Differentially methylated regions (DMRs) showed the different levels of methylation in promoters, CpG islands, and genes in CRC. In addition, gene expression and DNA methylation were integrated into a colon-specific regulatory gene network, detecting 8 epigenetically regulated gene modules which drive CRC through an underlying epigenetic mechanism. Interestingly, 2 of the colon-specific DNA methylation-regulated gene modules showed a significant predictive ability for the survival of an independent set of CRC patients. CONCLUSIONS The results of this study could open a new era and aid the development of novel therapeutic targets for the treatment of CRC patient.