Epigenetic Modifications in Tumor Suppressor Genes (TSG) 15Epigenetic mechanisms are reversible changes in DNA that modulate the
expression of various genes, without altering the DNA sequence. They occur
during development, differentiation, tumorigenesis, and aging as well as in
many other biological processes. They include changes in DNA and its
associated proteins such as the histones 1 .
The amino-terminal groups of histones have residues of amino acids that
can be modified by methylation, acetylation or phosphorylation inducing
changes in the structure of the nucleosomes. These changes regulate the
binding and activities of the transcription factors and other proteins that
interact with the promoter regions of specific genes, regulating the expression
of these genes. In this regard, numerous studies show a correlation between
increased acetylation of histones and increased transcriptional activity while
the deacetylation and methylation of histones is correlated with gene silencing
2 .
Despite this generality, some exceptions have been described such as
methylation of lysine 4 of histone H3 in active transcription regions that
promotes its acetylation 2 . Histone acetyltransferases (HATs) and histone
deacetylases (HDACs) are enzymes that mediate the acetylation and
deacetilacion process of histones, respectively.
In mammals, DNA methylation is an epigenetic mechanism that involves
the enzymatic addition of a methyl group to the carbon 5 of cytosine in DNA.
These epigenetic modifications occur in the dinucleotides CpG distributed in
the human genome with a rate five times higher in regions called “CpG
islands”. In general, CpG islands are located in the promoter regions of genes
and the methylation process regulates the transcription of these genes. DNA
methylation inhibits gene expression through the recruitment of repressive
proteins such as Methyl-CpG-binding proteins (MeCP) and proteins with a
domain of binding to methyl groups (MBD). Hypermethylation of promoter
regions is associated with transcriptional repression while hypomethylation is
generally correlated with gene activity.
DNA-methyltransferases (DNMTs) are the enzymes that carry out DNA
methylation. At least three functional DNMTs have been identified in
eukaryotic cells. DNMT1 preferentially methylates hemimethylated DNA and
participates in the maintenance of methylation patterns with each cell division
3 . DNMT3a and DNMT3b contribute to de novo methylation during
embryogenesis 4 . DNMT2 has no relevance in the DNA methylation
activity.
In normal cells, DNA methylation maintains gene silencing and
participates in development, genomic imprinting and X chromosome