Our body consists of various tissues such as skin, stomach, and liver, and these tissues consist of different types of cells. Although essentially all the cells have the same genetic information, cells acquire different characteristics that persist for a life time. This is because different types of cells have added different sets of stable marks to genes that should be used (expressed) and also to genes that should not be used. Epigenetics is the discipline that elucidates the characteristics of these marks. As symbolized by the fact that gastric cells cannot be transdifferentiated into skin cells, stable transmission in somatic cells is one of the major characteristics of epigenetic marks.
In a cell, DNA is present circling approximately twice around proteins called histones. Epigenetic marks consist of the mark on DNA (DNA methylation) and marks of histones (histone modifications) (Fig. ).
Fig. DNA methylation and histone modifications
As epigenetic marks, DNA methylation and histone modifications are known. DNA is methylated at cytosines at CpG sites.
DNA methylation is a chemical modification by a methyl group on cytosines at the CpG sequences of DNA. When a region that regulates gene expression (a promoter region) is methylated, the gene cannot be expressed (Fig. 1). DNA methylation status is precisely maintained after DNA replication (Fig. 2), and is a stable epigenetic mark (Ushijima et al., 2003).
DNA methylation is essential for development in higher organisms such as humans. In addition to specification of cellular types, DNA methylation is deeply involved in other biological phenomena, such as differential use of genes in a parent-of-origin-specific manner (genomic imprinting) and inactivation of one of the two X chromosomes in females (X chromosome inactivation). Furthermore, aberrant patterns of DNA methylation are observed in human diseases such as cancer.
Fig. 1. Inactivation of a gene by DNA methylation.
When a promoter region is methylated, the gene cannot be expressed.
Fig. 2. Maintenance of DNA methylation status
When cells divide, DNA is replicated. Although the newly synthesized DNA strands are unmethylated, DNA methyltransferase 1 (DNMT1) precisely maintains the DNA methylation status.
Aberrant DNA methylation and Cancer
Normal cells have genes that promote cell proliferation (oncogenes) and those that repress cell proliferation (tumor-suppressor genes). Distortion of genetic information (mutation) of oncogenes can result in constitutive activation of the oncogenes. In contrast, mutations of tumor-suppressor genes and also their deletion (chromosome deletion) result in their inactivation (Fig.). Both oncogene activation and tumor-suppressor gene inactivation can cause uncontrolled cellular proliferation.
In the 1990's, it was revealed that aberrant DNA methylation, in addition to mutations and chromosome deletion, can cause inactivation of tumor-suppressor genes (Ushijima, 2005 ). Until now, inactivation of many tumor-suppressor genes by aberrant DNA methylation was reported in various cancers. In some cancers such as gastric cancer, inactivation of tumor-suppressor genes by DNA methylation is more frequent than that by mutations or chromosome deletion (Ushijima and Sasako, 2004 ).
Fig. Three mechanisms of inactivation of tumor-suppressor genes.
Mutations, chromosome deletion, and aberrant DNA methylation are known as mechanisms for inactivation of tumor-suppressor genes. Aberrant DNA methylation causes inactivation of tumor-suppressor genes without any changes of genetic information of tumor-suppressor genes.