Methylation & Acetylation
Gene Regulation
Epigenetics is a field that I find fascinating and am dedicated to pursuing. I will be writing many posts on this topic in the future and I would like to start out with an explanation of what it is and how it works.
The formal definition of epigenetics is: a change in gene expression without alteration of the nucleotide sequence.
When most people think of DNA they most likely imagine chromosomes — but DNA only exists as a chromosome when the cell is actively dividing. Chromosomes are a highly packaged and condensed form of DNA where it is non-functional, this is the most efficient way to store it. DNA is squished too much as a chromosome to be active and producing protein.
Most of the time, the cell is not actively dividing and its DNA will be relaxed and strung out to fill the space within the nucleus. DNA needs to be strung out in order for it to produce a protein.
Within the DNA double helix there are base pairs, AT & CG which are connected to each other through hydrogen bonding. The sequence of base pairs corresponds to the protein that is produced from the gene because when the gene is transcribed there are polymerase enzymes that will attach themselves and read the gene three base pairs at a time. So polymerases read the sequence as AGG or CUG — this is called a codon and the sequence of that codon corresponds to a particular amino acid. For example the sequence CUG corresponds to leucine. As the polymerase reads the gene one codon at a time, it will produce a chain of amino acids which will condense upon itself and aggregate to form a three dimensional structure which we call proteins or enzymes.
So the production of proteins from our genes relies on the ability of the polymerase enzymes to attach to the gene and start reading it. All genes have a promoter sequence which starts right in front of the beginning of the gene, it is a particular sequence of its own that polymerase enzymes are programed to recognize; this is how polymerases know to start transcribing a gene.
If this promoter sequence is exposed, it will recruit polymerase to it and start transcribing (this is a very simplified version of what happens but you get the point). However if that promoter sequence is blocked or packaged up, polymerase can’t bind and no protein will be produced. These are the foundational ideas of epigenetic regulation.
Tags control gene transcription
The rate of gene transcription can be changed by the addition of tags to DNA or histone proteins. The most well studied of these tags is addition of a methyl group.
A methyl group is one carbon and three hydrogen atoms. These are supplied through the methyl cycle to methyltransferase enzymes. Methyl groups are added to cytosine nucleotides on what are called CpG islands. CpG islands are stretches of DNA that are mostly made out of C-G base pairs. When these CpG islands are near a promoter region of a gene they can become methylated and this can block polymerase enzymes from accessing the DNA & can slow transcription.
The addition of methyl groups to DNA are usually associated with a down regulation of transcription. Methyl groups can directly block the access of polymerase enzymes but they can also block transcription factors and other regulatory proteins from accessing the promoter region.
Genes are commonly thought of as an on/off switch but they should really be thought of as a dimmer switch. Genes will rarely be turned on or off completely, usually they are upregulated (producing more protein) or downregulated (producing less protein).
Another tag that is becoming pretty well studied is the addition of acetyl groups. Acetyl groups are made of two carbons, one oxygen and three hydrogens. These can be added to histone proteins. Histones are large protein complexes made of 8 smaller proteins stuck together. DNA wraps itself around these as a way to organize itself, the closer together the histones are the more condensed and inaccessible DNA will be.
DNA is negatively charged while histones are positively charged, this is why DNA has a high affinity for binding to them. However, the addition of an acetyl group to the histone will neutralize some of its positive charge, resulting in DNA having a lower affinity toward binding. The addition of acetyl groups is generally associated with an upregulation of a gene because it results in DNA disassociating from the histones, leaving it accessible for transcription by polymerase proteins.
Methyl groups can also be added to histone proteins on lysine and arginine residues. Lysine can hold up to 3 methyl groups and arginine can hold 2. The effects of histone methylation are very context dependent & can lead to either an upregulation or a downregulation depending on how many methyl groups are added, what residue they are added to, or what area of the histone they are present on.
Other tags like phosphoryl groups can be added to serine, threonine, or tyrosine residues and add a strong negative charge resulting in dissociation of DNA and gene upregulation.
Methyl groups and acetyl groups are just one aspect of epigenetic regulation of genes. I find these the most interesting because we can control them to some respect using diet and lifestyle. I look forward to discussing these topics and highlighting their role in metal disorders and cancer, among others.