Inflammatory bowel disease (IBD), which can increase the risk of colorectal cancer (CRC), includes two primary subtypes, ulcerative colitis (UC) and Crohn's disease (CD). Although several individual genes involved in inflammation or cancer characterization have been identified, it is still difficult to elucidate functional relationship details between the molecules underlying pathogenesis at the system level. The global effect of miRNAs on genes or their involved functions is also poorly understood. We first integrated genome-wide gene expression profiles and biological pathway information to explore the underlying associations among UC, CD and CRC at the function and gene level. After identifying the pathways regulated by miRNAs, a global map of miRNA-mediated pathway crosstalk shared by the three diseases was further constructed to vertically explain the links of three level alterations. The three types of diseases have close associations with each other at the levels of function, gene and miRNA regulation. Several key biological pathways are involved in the three diseases, related to the immune system and inflammation, metabolism, or cell proliferation and apoptosis etc. Moreover, miRNAs exhibit dominant effects on multiple pathways. It is worth noting that UC shows relatively close associations with CD and CRC at the three levels. Finally, the miRNAs could mediate the crosstalk within or between pathways. For example, hsa-miR-125b, hsa-miR-335 and hsa-miR-155 mediated the crosstalk between three metabolic pathways. The crosstalk within the Toll-like receptor signaling pathway could be mediated by hsa-miR-124, hsa-miR-146a and hsa-mir-221/222. Our results make sense for the prevention and treatment of intestinal-related chronic inflammation or cancer.
Breast cancer is a highly heterogeneous disease that is characterized by genetic and epigenetic aberrations; however, our knowledge of epigenetic alterations of breast cancer subtypes remains limited. Here, we portrayed and compared the alterations of six types of histone modifications and DNA methylation between two breast cancer subtypes, luminal and basal. Widespread subtype-specific epigenetic alterations were observed in both subtypes, which preferentially occurred within CpG islands (CGIs) and promoter regions. Specifically, aberrant DNA methylation was mostly located inside CGIs in luminal subtype, whereas in basal subtype it was principally located within CGI shores. Moreover, different types and combinatorial patterns of epigenetic alterations were found to occupy at promoter regions between these two subtypes. And these epigenetic alterations regulated corresponding gene expression in a synergetic way in both subtypes. Functional enrichment analysis highlighted that epigenetically dysregulated genes were significantly involved in the hallmarks of cancers, most of which were subtype specific. Even genes involved in the same hallmarks associated biological processes were affected by various types of epi-modifications in different subtypes. Finally, we revealed distinct patterns of oncogenic pathways activation in different subtypes and provided novel insights into subtype specific therapeutic opportunities. In addition, genes in the key signaling pathways were able to discriminate between disease phenotypes, and subtype-specific progression associated genes were identified. This study presents the aberrant epigenetic patterns of breast cancer subtypes at a genome-wide level, which will be a highly valuable resource for investigations at understanding epigenetic regulation of breast cancer subtypes.
DNA methylation is an essential epigenetic mechanism involved in transcriptional control. However, how genes with different methylation patterns are assembled in the protein-protein interaction network (PPIN) remains a mystery.
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