Epigenetics: interaction of DNA methylation and chromatin Epigenetics is a field where advances are being made daily. Epigenetics is defined as “heritable changes in gene expression that occur without a change in DNA sequence,” as stated by Dr. Alan Wolffe. A way in which we can understand this definition is by taking the analogy of a card game. The cards, the DNA sequence, have been dealt and will not change, however we need to understand how to play the cards, the rules, which is epigenetics.
The guidelines can vary and completely change the way the card game is played and who comes out on top. The rules that are studied and understood through this research paper are those of DNA methylation and chromatin. These changes can produce large variations in the gene expression of cells while maintaining the same DNA sequence. Since all the somatic cells in our body contain the same DNA, the difference lies in the genes that are expressed. Most of the time, the majority of genes are regulated by repressing transcription, so the genetic information is used selectively.
Epigenetics covers a wide field; contained in it are “DNA methyltransferases, methyl-CpG binding proteins, histone modifying, enzymes, chromatin remodeling factors, transcriptional factors and chromosomal proteins” as well as “centromere, kinetochore and telomere. ” Chromatin is made of DNA packed around histone proteins and it also contains non histone proteins. The histones maintain the DNA shape and structure. This chromatin can occur in different forms. One is euchromatin, here the chromatin is not coiled so tight, but expanded so there is room for transcription factors to come in and there is a lot of actively transcribed genes.
This is possible because of the exposure of the sequences when the chromatin is stretched out. Conversely there is a state in which the chromatin is packed and coiled, and there is no access to the sequence so transcription does not take place. This state is called the heterochromatin. Something to note here is, not only the sequence of DNA is passed down from parent cells to the daughter cells, but there is also these different states of the chromatin that are passed down in the same way and conserved! So how is DNA methylated?
Methylation takes place at the 5’ C and 3’G base pair. More specifically at the cytosine carbon and the same in the complimentary strand to this. This is not only done at a few sites, rather about 60-90% of these carbons are methylated! An area that is highly methylated will actually help to repress gene expression if it is methylated at CpG island sites, where transcription beings. DNA methylation can also result in inactivation of tumor suppression in cancer cells when it becomes abnormal, due to this, epigenetics becomes a strong focus point when studying cancer.
Also this leads to the cytosine’s being replaced by a thymine, leaving behind a dangerous T-G pairing which will be inherited and passed down through laterdivision. Another way this epigenetic phenomenon is benefitted from is its use in gene therapy. When foreign genes are used into a new host, they are methylated and thus suppressed as a “host defense mechanism. ” There are actually enzymes involved in the methylation, they are called, as one may be able to guess, DNA methyltransferases. There are two kinds of this enzyme the DNMT1 (maintenance) and de novo methylase.
The first kind is responsible for methylating DNA that has one side already methylated, because it is a new daughter strand. The other methyltransferase is the one which creates the hemi-methylated DNA that the maintenance methyltransferase works on. The opposite of this, which would be demethylation, is not quite understood, but there are two possible manners in which this can take place. The first would be that this is not something that is conserved when the DNA is replicated and the second is more active, in which a DNA demethylase (has not been discovered) does the job.
Just as there are enzymes that take care of methylating the DNA there are those that work to modify the histones. By acetylating histones there are more gene expression possibilities, this too serves to help open the chromatin structure up so that machinery can access it. Histone acetyltransferase (HAT) acetylates histones and uncoils DNA giving an open chromatin structure. Histone deacetylases (HDAC) on the other hand causes tight coils and a closed chromatin structure, repressing gene expression. There is a connection between cells that are too deacytlated and cancer cells because the cells become silenced.
HDAC will form transcriptional co-repressor complexes, two of which are the SIN3 and the Mi2-NuRD. The first of these is involved in interactions with chromatin. This is a representation of the complexes that are formed, you can see the HDAC components in the two complexes. The sin3 complex is recruited to methylated DNA by interacting with the top groups pictured in the first image. The second image is localized to methylated DNA regions when the MBD3 interacts with MBD2. Chromatin remodeling is the readjusting of the nucleosome positioning and conformation.
The nucleosome is what the chromatin is made up of, it contains 146 base pairs of 2 superhelical turns of DNA that are wrapped around 8 histones. There are ATP dependent complexes that do this task, i. e. SWI/SNF and ISWI families. They are generally involved in gene transcription and can initiate it. The first complex is incharge of activating gene expression, the RSF initiates the transcription. They are very complicated complexes and are made up of many subunits as the image above clearly shows. Each part has an important rol and interaction that allows the unit to function properly.
The CAF1 complex is linked to chromatin assembly in DNA replication and the other maintains heterochromatin. As we can see there is a lot to epigenetics and much more to learn. The various parts of DNA are regulated closely through different avenues that allow certain genes to be expressed. We looked at DNA methylation, histone acetylation and chromatin remodeling to get a closer look at how such processes are completed. There is a long future for further study in this field and many possibilities to cure diseases such as cancer.