Eric Samorodnitsky, Emily Ghosh, Sahana Mazumder and Sibaji Sarkar
Binding of activators and repressors plays a significant role in transcriptional regulation of gene expression. The systems biology approach has been applied to predict and determine the efficiency of this process; however, most of the work is done in prokaryotic systems. Epigenetic regulation provides another dimension of transcriptional regulation, which does not involve changes in the coding region of genes. Methylation of specific CpG residues in the CpG islands of DNA by the enzyme DNA methyl transferase 1 (DNMT1) causes gene silencing. In cancer cells, the enzyme DNMT1 is highly expressed, and the methylation level at specific sites of genes, including tumor suppressor genes, is elevated. This results in the silencing of tumor suppressor genes for carcinogenesis. However, it is not known whether the increase in DNMT1 expression is proportional to the increase in the level of methylation. This paper developed a systems biology approach to determine whether DNMT1 acts more efficiently in cancer cells than in normal cells. The cooperativity of DNMT1 binding to eight selected genes was determined in chronic lymphocytic leukemia (CLL) cells using a modified Hill equation and compared these values with those obtained from normal lymphocytes and granulocytes. The cooperativity of DNMT1 was found to be positive in four cancer-associated genes, whereas their values were negative in both normal lymphocytes and granulocytes. These results show for the first time how to apply systems biology in the analysis of transcriptional gene regulation. This approach will be beneficial in determining the efficiency of genome-wide methylation in development and in diverse types of diseases.