DNA Methylation – How Does It Affect Gene Expression?
Epigenetics is the study on how the environment and certain behaviors can affect how our genes work. DNA methylation and histone acetylation are examples of epigenetic changes.
Studying these epigenetic changes can give us insight about our genes and potentially use them to better our health. DNA methylation, a type of epigenetic change, has shown a lot of potential as a biomarker for disease-associated changes, which shows how much we can learn from this topic alone.
What is DNA methylation?
In terms of biochemistry, DNA methylation is an epigenetic process that involves the transferring of a methyl group to the cytosine ring of DNA. The process is involved in embryonic development, genomic imprinting, and regulating gene expression.
To put it simply, methylation of DNA is essential to the body since it affects our genes. It plays a big role in the development of the human body. In fact, a study even shows how it affects the aging and development of the prefrontal cortex which is an essential part of the human brain.
Further studies also show that both Dnmt3a and Dnmt3b DNA methyltransferases are important for mammalian development and de novo DNA methylation . Some studies even cover genome-wide DNA methylation involving embryonic stem cells.
Besides informing us about the function of methylation in normal development, studying methylation may give us insights about multiple diseases ranging from common diseases to more complex ones like cancer and autoimmune disorders. This just shows how vast the scope of the process is and how important it is to our health.
How is DNA Methylation Used In DNA Repair?
To understand how DNA Methylation is essential in DNA repair, we have to understand what DNA is, how it works, and how it gets damaged in the first place.
What is DNA?
DNA (deoxyribonucleic acid) is a hereditary material found in organisms that contains the biological information or developmental instruction of an organism. It contains information needed to develop th organism. It is passed one from the adult to their offspring through the reproductive process.
This information is stored as code made up of 4 bases: G (Guanine), C (Cytosine), A (Adenine), T (Thymine). In the human genome, DNA is made up of nearly 3 billion bases which are nearly identical in at least 99% of the human population.
These bases combine to store genetic information that holds the traits and properties of the organism. The order can determine what kind of information they have, which could be understood as being similar to how humans construct words from letters.
How does DNA get damaged?
Being made up of chemical bases, DNA is susceptible to chemical reactions. Some reactions can cause damage to the genomic DNA causing mutations and disease.
There are two main types of DNA damage: exogenous damage and endogenous damage. Exogenous damage to DNA can come from the environment, like UV radiation and gamma rays, while endogenous damage can be caused by metabolic processes, like reactive oxygen species (ROS) or by the errors which may happen during DNA replication.
How is DNA repaired?
There are many ways our body repairs our DNA, one such method is a direct reversal, which is the specific repair of the damage to the DNA molecule without resynthesizing a new base pair. Direct repair has been shown to be involved in specific types of DNA damage such as UV radiation.
A more general way of repairing DNA that relates to DNA methyltransferases and patterns of dna methylation is excision repair. Excision is one of the most common DNA repair processes and it can be used in a lot of cases. The damaged part of the DNA is removed either in the form of nucleotides or free bases, which allows new bases to replace them.
How does DNA Methylation fit into this?
There are three types of excision repair: mismatch repair, base excision repair, and nucleotide excision repair. One study shows a link between DNA Methylation and base excision repair, particularly mediated by Thymine DNA Glycosylase (TDG). TDG is an enzyme known for catalyzing the first step in the base excision repair.
Additionally, the same study also covers how TDG has a role in protecting the CpG islands from hypermethylation which may be linked to cancer and tumor suppressor genes.
Base Excision Repair (BER) can correct damages to the DNA with oxidation, alkylation, and deamination. The damaged bases are identified and replaced, repairing the DNA. One study on BER indicates that the process is involved by using related pathways that may have roles in preventing cancer, aging, and neurodegeneration.
A study published in Nature magazine shows that one of these pathways show the dynamic modifications of Cytosine with the TDG and DNA methylation as part of the process.
It starts with cytosine turning into 5-Methylcytosine (5mC) by DNA methyltransferase. 5-Methylcytosine undergoes oxidation turning into 5-Hydroxymethylcytosine (5hmC) and then 5-fluorocytosine (5fc). This 5fc is excised by TDG, forming an abasic site which prompts the start of BER.
Although this does not show that specific DNA methylation is directly involved with BER, it does show that its byproducts of turning cytosine into 5 methyl-cytosines implies that there may be a relationship between TDG and DNA methylation.
Additionally, there have been studies that show how DNA repair can affect DNA methylation as well. A study on the DNA repair of the kidney states that impaired DNA repair may alter DNA methylation and other epigenetic changes.
So while evidence suggests a relationship between DNA methylation on DNA repair, further research is needed to clarify how directly DNA methylation is involved in the DNA repair process.
How Does DNA Methylation Work?
Now that we have a better understanding of what DNA is as well as the role of specific DNA methylation, we can now have a better understanding of how it works and how it affects the body in the grander scheme of things.
As explained before, our DNA is made up of 4 bases: A (Adenine), T (Thymine), G (Guanine), C (Cytosine). DNA methylation is commonly the methylation of Cytosine which alters the genes into methylated DNA.
According to a study  published in Nature, DNA methylation occurs on cytosines preceding a guanine nucleotide or CpG sites. When it is catalyzed by DNA methyltransferases (Dnmts), this triggers the addition of a methyl group (-CH3) in cytosine, creating 5-Methylcytosine.
One common process of this is the conversion of cytosine into 5-Methylcytosine through the addition of a methyl group to cytosine via a group of enzymes called DNA methyltransferase. 5-Methylcytosine helps regulate gene expression which can possibly alter the function of the DNA.
However, 5-Methylcytosine can be turned back into cytosine through a process called DNA demethylation. As the name implies, DNA demethylation removes the methyl group added in 5-Methylcytosine which reverts it back into cytosine through an enzymatic process.
How Does DNA Methylation Affect Gene Expression?
Now that we know how specific DNA methylation and demethylation works, it’s time to figure out the processes that affect gene expression. We know that DNA methylation is involved with the regulation of gene expression, but how exactly does it do this?
Methylated DNA represses the expression of genes by inhibiting the binding of transcription factors or by recruiting proteins involved in gene repression. It involves a plethora of different proteins like methyl-binding protein MeCP2, MBD1, MBD2, MBD3, MBD4, and histones like histone h3 which does show some links to DNA methylation and some diseases like hepatocellular carcinoma (HCC).
CpG islands are regions comprising stretches of DNA containing high amounts of CpG dinucleotides. These “islands” are often associated with housekeeping genes.
The CpG Islands can serve as markers for the genes of organisms, and they often contain 5-methylcytosine in their genomes. And a comprehensive study about CpG island states that it holds a lot of function for X-chromosome inactivation, gene silencing, and imprinting. In fact, it has been shown that the CpG methylation of these regions can silence gene expression during early embryonic development.
A lot of information about these and their role in gene expression is still unknown. The changes in gene expression in the CpG Islands suggest that the methylation of CpG islands can stably silence gene expression and impair the binding of transcription factors.
Are There Negative Types of DNA Methylation Patterns?
There are. One type of DNA methylation which can have negative effects is de novo methylation. It is a process where methyl groups are added into unmethylated DNA at certain CpG sites. The process is catalyzed by DNMT3A and DNMT3B.
These types of methylation patterns are considered to be undesirable in a lot of differentiated cell type since they need precise maintenance of that DNA pattern. But this is just a case to case basis and just like with a lot of body processes, specific DNA methylation can either be good or bad depending on the context and situation.
DNA methylation and cancer
Recent studies have shown that the patterns of global DNA methylation have the potential to be used as biomarkers for cancer. The reason for this is that carcinogenesis can be followed by drastic changes within the cell through this process which makes it so that looking out for its patterns is a possible method for early detection of cancer.
Another study regarding ovarian cancer states the possibility of using DNA methylation as a form of diagnostic tool for this type of cancer. Early diagnosis of ovarian cancer could possibly save lives since a lot of fatalities regarding ovarian cancer stems from late diagnosis.
Lastly, a study focusing on pituitary neuroendocrine tumors delved into the possible effects that DNA Methylation has on tumor suppressor genes (TSGs). This study suggests that DNA methylation may have a down regulation effect on the gene expression of some TSGs.
In short, studying more about DNA methylation may help us fight cancer in the future which is a promising prospect.
Gene Methylation’s Correlation With Social and Economic Factors
Asides from affecting the gene body and our genomic DNA, DNA Methylation also has some correlations with the social and economic life of people as well. A methylation analysis published in the International Journal of Epidemiology states the SEP (socio-economic position )of individuals or something related to it may have some effect on DNA methylation variation.
Other studies also back this up and state that the early life environment of an individual can affect their DNA methylation later on in life, with some evidence suggesting the DNA methylation alterations as a response to early socio-economic adversity experience in early life.
Lastly, a study by a team in the UCL Institute of Child Health in London, the University of British Columbia in Vancouver, and the McGill University in Montreal, showed some interesting results which may imply a relationship between the genome-wide biochemistry of our DNA and the economics of early life.
In this study, blood samples conduction in 40 UK participants with varying standards of living to determine if there were any differences in their DNA methylation analysis. Measurements were analyzed with control regions of over 20,000 genes.
If DNA acts like words and the human genome as sentences, then the researchers state that DNA methylation is similar to punctuation marks in your DNA which helps you read the genome more accurately. They found over 6000 gene control regions which help them clearly differentiate the 40 participants from one another.
What they found really surprising was that gene promoters of their subjects showed a major difference between childhood and adulthood. With 1252 gene promoters being relating to the living conditions of their subject’s childhood and 545 gene promoters for adulthood.
This shows that childhood living conditions could have a link with an early socio-economic environment. The researchers expressed that their research is only just the beginning and they can’t tell precisely which epigenetic patterns and methylation patterns can be associated with particular diseases. It’s merely a foothold and they hope that future research can lead to better results.
DNA methylation is an interesting topic that has been covered by some research. It is a fundamental epigenetic process, and it has proven itself very valuable in a lot of ways. However, despite all of its studies, a lot is left to be desired for its potential applications in medicine.
Hopefully, by reading this article shined a little bit of light on the complicated topic that is DNA methylation. It’s not something you get to see every day but knowing a little bit about it can help in the long run especially if you’re dealing with epigenetic drugs that treat cancers and neurological diseases.
Frequently Asked Questions
Epigenetics is a study that focuses on how our behavior and our environment affects our genes.
DNA stands for deoxyribonucleic acid which contains the genetic information about a certain species. It’s often referred to as the genetic blueprint of an organism since it contains information needed to build that organism in the first place.
It is an epigenetic process that adds a methyl group to a DNA base to modify the function of a gene. This process can affect our body at the molecular level since it is involved in repressing gene expression.
Yes they do. In certain studies, researchers look for changes in methylation levels to determine whether their hypothesis is correct. A good example of this is research that focuses on auto-immune diseases that find the correlation or role of DNA methylation in SLE risk and disease.
Yes it can. Some studies even state its potential as a diagnostic tool for cancer which could help save lives.
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