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  • DNA and Protein Methylation

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    In eukaryotic cells, genomic DNA is wrapped around histone proteins to form nucleosomes. Each nucleosome consists of a stretch of 147 DNA base pairs wrapped around a histone octamer. Histones, especially the amino-terminus tail can also be modified in a number of ways, in addition to methylation. Such alterations include the addition of acetyl groups (acetylation), phosphate groups (phosphorylation), ubiquitin proteins (ubiquitylation), and SUMO proteins (sumoylation). These modifications to histone proteins and DNA can either inhibit or promote coiling or condensation of the chromatin. Collectively, these epigenetic modifications lead to changes in chromatin organization, which in turn determines the expression of the associated genes, ultimately influencing an organism’s growth and development. For example, DNA methylation plays an important regulatory role in determining the fate of embyos. Similarly, genomic imprinting is a process that controls the expression of a gene contingent upon the parental origin of the allele. Typically, the non-methylated allele is expressed while the other methylated allele is silenced. In mammals, targets of DNA methylation can range from individual genes to entire chromosomes. During development, for example, DNA methylation plays a major role in inactivating one of the two copies of the X chromosome in female mammals.

    DNA methylation and gene silencing have also become determinants of disease progression and the enzymes involved in DNA and histone modification have become drug targets. For example: Sep9 gene methylation is a predictor of colorectal cancer, and numerous other gene targets are being validated as biomarkers. Similarly, several pharmacological drugs are currently in the market that can modulate both DNA and histone methylation for treatment of MLL, MDS and AML.  

    In addition to transcriptional control and allele silencing, methylation or hydroxymethylation of bases within a restriction enzyme recognition sequence affects recognition and subsequent cleavage by the enzyme at that location (3). This property is useful for determining differential modification of a gene in complex genomic DNA.

    References

    1. Cooper, Geoffery M. The Cell: A Molecular Approach. 4th ed. Washington D.C.: ASM Press, 2007.  281-3.
    2. Cooper, Geoffery M. The Cell: A Molecular Approach. 4th ed. Washington D.C.: ASM  Press, 2007.  286.
    3. Hoffman, J.L. (1986) Biochemistry, 25, 4444-4449.PMID: 3530324
    4. Tan, M et al. (2011) Cell, 146 (6), 1016-1028. PMID: 21925322