Harris KhanA gene promoter is a region of DNA which acts like a switch to “turn a gene on”. The more methylated the promoter is, the more it is “turned on”. RNA is a key molecule found in cells responsible for a variety of biochemical processes that are essential to the integrity of the cell (D’Aquila, 2017). Hypomethylation (reduced levels of methylation) of the RNA gene promoter has been observed in many different types of cancer (Ghoshal K, 2004). Additionally, hypermethylation (high levels of methylation) of the RNA promoter gene has also been associated with Alzheimer’s disease (Pietrzak M, 2011).
Within ageing research, there is growing interest in the RNA promoter and it’s methylation status. This is because of it’s association with age related disease (D’Aquila, 2017).
What Exactly is DNA methylation and Why is it Important?
DNA Methylation is used to control gene expression and maintain stability in the genome. Methylation refers to the addition of a methyl group via a covalent bond at the fifth carbon on a cytosine base within a CpG dinucleotide giving rise to 5-methyl cytosine (Jin, 2011). A CpG dinucleotide is a site where a cytosine base lies next to a Guanine base in the DNA sequence connected via a phosphodiester bond (Jr, 2017). Hypermethylation of CpG sites is often associated with transcriptional repression, conversely, hypomethylation is associated with transcriptional activation (Bird, 1992). DNA methylation prevents the binding of transcription factors to the DNA or leading to transcriptional silencing (Bird, 2001). Special enzymatic molecules called DNA Methyltransferases (DMNT1, DMNT3a and DMNT3b) catalyse DNA methylation. This is outlined in figure 1.1 (Cheng, 2008).
Figure 1.1: DNA Cytosine ring showing the process in which the DNA methyltransferase enzyme (DNMT) facilitates methylation on the Carbon 5 position. Figure Taken from (Cheng, 2008).
DNA methylation occurs throughout life and is essential for normal development beginning during embryonic development. DNA methylation is carried out in two different forms. Maintenance methylation and de novo methylation. The most common enzyme within maintenance methylation is DNA methyltransferase 1 (DNMT1) which is used to methylate hemi-methylated CpG dinucleotides in the genome, ensuring reformation of parental DNA methylation pattern which can be lost in the daughter DNA (Chen T, 2006).Within de novo methylation however, the DNMT3 family of catalytic enzymes are present. These are DNMT3a and DNMT3b which can newly methylate cytosine groups. Predominantly occurring within the embryo development stages of a mammal’s life cycle. There is also another enzyme present within the DNMT3 family known as DNMT3L which is largely inactive but has been observed to stimulate methylation of DNA by DNMT3a when they are both co-expressed (D’Aquila, 2017). The difference between de novo and maintenance methylation is illustrated below in figure 1.2.
Figure 1.2: De novo methylation vs maintenance methylation. The pale blue segments illustrate substrate sequences (mainly CpG sites) whilst the turquoise shapes represent methyl groups on cytosines. After replication or repair the duplex is methylated on a single strand only. Figure taken from (Cheng, 2008).
References
Bilian Jin, Y. L. (2011). DNA Methylation: Superior or Subordinate in the Epigenetic Hierarchy? Genes & Cancer, 607–617.
Bird. (1992). The essentials of DNA methylation. Cell 70, 5-8.
Bird, A. (2001). Methylation talk between histones and DNA. Science , 2113–2115.
Chen T, L. E. (2006). Establishment and maintenance of DNA methylation patterns in mammals. Current Topics in Microbiology and Immunology, 179-201.
D’Aquila, P. (2017). Methylation of the ribosomal RNA gene promoter is associated with aging and age related decline. Aging Works, 966-975.
Ghoshal K, M. S. (2004). Role of human ribosomal RNA (rRNA) promoter methylation and of methyl-CpG-binding protein MBD2 in the suppression of rRNA gene expression. Journal of Biological Chemistry, 6783–6793.
Jr, W. C. (2017). Medical Definition of CpG . Retrieved from Medicine Net: https://www.medicinenet.com/script/main/art.asp?articlekey=26443
Loukas Zagkos, M. M. (2019). Mathematical models of DNA methylation dynamics: Implications for health and ageing. Journal of Theoretical Biology, 184-193.
Pietrzak M, R. G. (2011). Epigenetic silencing of nucleolar rRNA genes in Alzheimer’s disease. PLoS ONE, e22585.
Xiaodong Cheng, a. R. (2008). Mammalian DNA Methyltransferases: A Structural Perspective. Structure, 341-350.
