DNA methylation is a biochemical process that is important for normal development in higher organisms. It involves the addition of a methyl group to the 5 position of the cytosine pyrimidine ring or the number 6 nitrogen of the adenine purine ring (cytosine and adenine are two of the four bases of DNA). This modification can be inherited through cell division.
DNA methylation is a crucial part of normal organismal development and cellular differentiation in higher organisms. DNA methylation stably alters the gene expression pattern in cells such that cells can “remember where they have been” or decrease gene expression; for example, cells programmed to be pancreatic islets during embryonic development remain pancreatic islets throughout the life of the organism without continuing signals telling them that they need to remain islets. DNA methylation is typically removed during zygote formation and re-established through successive cell divisions during development. However, the latest research shows that hydroxylation of methyl group occurs rather than complete removal of methyl groups in zygote. Some methylation modifications that regulate gene expression are inheritable and are referred to as epigenetic regulation.
In addition, DNA methylation suppresses the expression of viral genes and other deleterious elements that have been incorporated into the genome of the host over time. DNA methylation also forms the basis of chromatin structure, which enables cells to form the myriad characteristics necessary for multicellular life from a single immutable sequence of DNA. DNA methylation also plays a crucial role in the development of nearly all types of cancer.
DNA methylation at the 5 position of cytosine has the specific effect of reducing gene expression and has been found in every vertebrate examined. In adult somatic tissues, DNA methylation typically occurs in a CpG dinucleotide context; non-CpG methylation is prevalent in embryonic stem cells.
In biology, histones are highly alkaline proteins found in eukaryotic cell nuclei that package and order the DNA into structural units called nucleosomes. They are the chief protein components of chromatin, acting as spools around which DNA winds, and play a role in gene regulation. Without histones, the unwound DNA in chromosomes would be very long (a length to width ratio of more than 10 million to one in human DNA). For example, each human cell has about 1.8 meters of DNA, but wound on the histones it has about 90 micrometers (0.09 mm) of chromatin, which, when duplicated and condensed during mitosis, result in about 120 micrometers of chromosomes.
Histone methylation is the modification of certain amino acids in a histone protein by the addition of one, two, or three methyl groups. In the cell nucleus, DNA is wound around histones. Methylation and demethylation of histones turns the genes in DNA “off” and “on”, respectively, either by loosening their tails, thereby allowing transcription factors and other proteins to access the DNA, or by encompassing their tails around the DNA, thereby restricting access to the DNA. This is true in most cases.
This modification alters the properties of the nucleosome and affects its interactions with other proteins.
“Breaking the Silence: The rise of epigenetic therapy,” Journal of the National Cancer Institute, Garber 2002
Workman said he believes that epigenetic gene silencing is as much a driving force in cancer as genetic mutation. “This is just a major, major way in which tumors turn off genes they don’t want expressed,” he said.
This statement would have been heresy just a few years ago, but most scientists now accept that remodeling of chromatin is central to cancer. Chromatin consists of proteins called histones, which form nucleosome beads looped and linked by DNA. Methylation and histone deacetylation function to bind DNA tightly to histones and prevent the transcription and expression of tumor suppressor genes. (See News, June 5, p. 793.) Reverse this process by relaxing chromatin, the theory goes, and gene expression will drive cancer cells to commit suicide or to senesce. Researchers are testing this theory with methylation inhibitors and histone deacetylase (HDAC) inhibitors.