Abstract
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.
Highlights
Transcriptional regulation by an epigenetic mechanism is a major process that affects how gene expression is controlled in cells without altering the coding region of the gene
As described in the methods, all results were converted to quantitative levels of DNA methyl transferase 1 (DNMT1) expression, and the ratio of methylation levels to the DNMT1 expression levels was calculated in chronic lymphocytic leukemia (CLL), normal lymphocytes, and normal granulocytes
The efficacy of methylation (n) was determined by using a modified Hill equation for 8 candidate genes in CLL cells, normal lymphocytes, and granulocytes. Building on this previous work, this paper calculated the concentration of DNMT1 enzyme in CLL lymphocytes and compared them to normal lymphocytes and normal granulocytes
Summary
Transcriptional regulation by an epigenetic mechanism is a major process that affects how gene expression is controlled in cells without altering the coding region of the gene. One of the epigenetic modifications that alters transcription is methylation at CpG residues in DNA. Histone modifications, such as methylation and acetylation, regulate transcription by changing open or closed chromatin structures. These modifications play a huge role in embryogenesis, stem cell biology, cellular development, and differentiation [1,2,3]. Aberration of this regulation generates many types of disorders and diseases [4]. The enzyme DNA methyl transferase 1 (DNMT1) incorporates methyl groups onto the cytosine of CpG residues such that the methylation on the daughter strand matches the methylation on the template strand
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