This video (Citation 14) , part of PBS' NOVA series, highlights many of the real world applications of epigenetics. The research it portrays represents the field's cutting edge, illuminating the potential for this area of study. Certain examples presented in the video, along with others that were not discussed, crystallize epigenetics' role as the bridge between nature and nature. You are born with your genome, but as you age, the decisions you make dictate how your genome will ultimately affect you. The lab mice at Duke University, for example, were fed either low-methyl group or high-methyl group diets. The former suffered from debilitating obesity, while the latter lived a regular life. |
Scientists are linking epigenetics to various biological phenomena and applications. Certain new and potential examples, and their impacts, will be discussed here. Economic and political impacts will also be discussed here.
Cancer Development & Treatment
Researchers across the globe have begun to investigate the links between epigenetic changes and cancer. Cancer-causing changes, like all epigenetic changes, fall into the two main categories: DNA methylation and histone modification. This section discusses the role of these two mechanisms in causing cancer. Various modifications to specific sites have been linked to the proliferation of cancer. For example, hypoacetylation of the H4 histone is present in various cancers, including testicular cancer and some types of leukemia. The list of amino acid residues and/or histones that are linked to a cancer is enormously long. However, analysis of these specific scenarios has rendered patterns for carcinogenesis. For example, modifications to histones relating to gene promoters are one of the most prominent paths to the development of cancer. Such modifications have a prominent link to cancer: the gene for cyclin-dependent kinase inhibitor. This molecule is one of the checkpoints that helps to regulate cell division. If it does not function properly, cells may divide uncontrollably, leading to the creation of a tumor. In addition, various observations of histone modifications and their connections to cancer have revealed that, as a general rule, inhibiting deacetylation suppresses the development of cancer. Various drugs capitalize on this trend to treat cancers (Citation 20).
DNA Methylation, too, can influence the development of cancer. Tumor cells exhibit two main traits related to methylation: (1) global hypomethylation and (2) local hypermethylation at tumor-suppressor genes and promoters. First, cancerous cells have 20-60% fewer 5'-methylcytosines than normal cells. Second, hypermethylation has been studied in more detail and is more fully understood. Once again, various specific examples of genes which undergo methylation modifications and are linked to cancer have been identified. However, patterns have also been found. For the most part, DNA hypermethylation occurs in the promoter regions of tumor-suppressor genes. Research has determined that in different cancers, different genes are hypermethylated. These patterns allow for specific cancer treatments, as the modifications may be reversed with the proper enzymes (Citation 20).
Alternative manners of gene expression alteration have been investigated, such as the deregulation of microRNA (miRNA). miRNA is a short sequence of RNA, which regulates various cellular functions, including cell differentiation and apoptosis (programmed cell death). Therefore, the alteration of miRNA could affect the development of cancer. Research suggests the factuality of this idea, as miRNA expression differs between normal cells and tumor cells. Ultimately, though, an alteration to miRNA-coding genes seems to be related to their hypermethylation, further illuminating the potential of this variant of modification (Citation 20).
This figure depicts the differences in cell methylation between normal cells and cancerous cells (Citation 20).
Cancer Treatment
As
researchers and doctors develop a better understanding of cancer's
relation to these epigenetic changes, they have begun to take advantage
of the link. DNA methylation provides a promising avenue for improved
methods of determining one's risk status for cancer, detecting the
disease, and monitoring it (Citation 20).
Each cancer has hypermethylated genes specific to it, which can potentially allow for improved diagnosis of cancer. Doctors could obtain a relatively small quantity of DNA and expose it to a bisulfite treatment, which changes the normal cytosines to thymines, while methylated cytosines do not change. This simple and efficient process opens a new window to patients, who can now learn of their disease significantly earlier, allowing further treatment to go forward (Citation 20).
DNA methylation, as a cause of cancer, is unique in that it can be reversed, creating the possibility for therapies. In vitro attempts to demethylate hypermethylated genes have been successful. If this technique can be applied in the body, then the aforementioned demethylating agents have enormous potential as drugs. These drugs do not simply remove the methyl group, but instead replace the entire natural cytosine with an analogous structure. The next time the cell replicates and a methyltransferase attempts to attach a methyl group to the analog, it traps the enzyme and targets it for destruction, thereby ending the cycle of division and methylation. However, these drugs cannot be applied to specific portions of the genome, which can lead to global hypomethylation. This, too, is an undesired outcome, as it is connected to aberrant gene expression and chromosomal instability. Currently, drugs known as Vidaza and Decitabine are DNA methylation inhibitors that have been approved by the FDA (Citation 20).
Cardiovascular Disease
The nature of cardiovascular disease (CVD) and its related ailments lend themselves to epigenetic investigation. CVD stems from atherosclerosis, which, simply put, is the accumulation of lipoproteins in the arteries. Eventually, the accumulation reaches a tipping point, resulting in one of the branches of CVD. It is a well-known fact that diet and lifestyle play a crucial role in the development of this disease. Therefore, CVD provides an excellent opportunity to investigate how environmental factors affect the genome (Citation 20).
Both global hypo- and hypermethylation of the DNA in vascular tissue may induce atherosclerosis. Diet plays a significant role in this, as it does in many other epigenetic areas. Cholesterol, for example, helps to determine the well-being of one's vascular system. High density lipoproteins (HDL) do not promote aberrant methylation patterns and are known to protect from the development of atherosclerosis. On the other hand, low density lipoproteins (LDL) and very low density lipoproteins (VLDL) promote hypermethylation, thereby encouraging the development of CVD (Citation 20).
Other Diseases
Epigenetics is involved in many other lesser-known diseases. This section will discuss three examples and explaing their epigenetic link. The three highlighted diseases reveal the broad spectrum covered by epigenetic diseases.
Rett Syndrome
Rett Syndrome (RTT) is a disease stemming from a mutation related to methyl-CpG-binding protein 2 (MECP2). The effects of this syndrome include the loss of intellectual functions, loss of motor skills, nervous system functions, and certain autistic characteristics. It is nearly exclusive to females and has an occurrence of approximately 1 in 15,000. Rett syndrome falls under the epigenetic category as MECP2 binds to methyl-CpG dinucleotides, thereby playing a role in repressing transcription and altering chromatin structure (Citation 20).
Cockayne Syndrome B
Cockayne Syndrome B (CBS) is a DNA repair disorder that also has chromatin structure implications. Its symptoms include stunted growth, skin photosensitivity, thin hair, and a prematurely aged appearance. CBS results from mutations affecting a protein known as ERCC6, which plays two significant roles. First, it belongs to a nucleotide excision repair (NER) pathway, which removes damaged DNA caused by exposure to UV radiation. Second, ERCC6 encodes a specific DNA-dependent ATPase, which wraps around DNA and, through ATP, can alter the structure of the of a nucleosome (Citation 20).
Rubenstein-Taybi Syndrome
Rubestein-Taybi Syndrome (RSTS) has to do with the modification of histones. It is an "autosomal dominant congenital malformation and mental retardation" (Citation 20). It has a frequency of about in 125,000 individuals. RSTS can cause, among other things, cardiac defects and malformations to the toes, fingers, and face. Furthermore, individuals with this syndrome are 350 times more likely to develop a tumor. Mutations to either the CREB-binding protein or a protein known as EP300 cause the disease. Both of these proteins play a role in regulating transcription and gene expression. They accomplish this through the recrutiment of the pol II complex to the promoter and through histone acetylation (Citation 20).
Tissue Engineering
Epigenetics could potentially play a huge part in the regeneration of tissue. Currently, scientists face numerous obstacles in the field of tissue engineering. Current processes fail in reproducibility, efficiency, speed and optimization. Other problems relate chemical factors that affect development, organization, differentiation and growth. Epigenetics could potentially assist in overcoming these scientific barriers by using methylation. DNA methylation not only alters gene expression but also "functions as a cellular memory" (Olek and Beck 166) through methylation of inactive genes. This "memory" is important because cells preserve their differentiation statuses, which, using demethylation processes, can be activated, thus overcoming the current problems of cell differentiation. In order to understand this "memory," DNA methylation patterns can be sequenced using a simple bisulfite treatment on DNA. Bisulfite sequencing provides us with the methylation pathways and can tell us which stage of differentiation a cell is in. Understanding the epigenetic influences on cell memory can yield efficient, reproducible methods of tissue engineering that could completely reshape the way we approach this field today. Strong methods in this field have the potential to make tissue on the large scale, and could even lead to the reconstruction of entire organs (Citation 4) .Wider Impact: Economic & Political Implications
Like most biotechnological sciences, the impacts of epigenetics will likely be felt far beyond the world of science.
Economic Issues
As interest in the field of epigenetics grows, a new market is opening up for investors. The Cancer Genome Atlas, a pilot project with the goal of mapping out epigenomic changes that cause some cancers, received $50 million each from two institutes: the National Cancer Institute and the National Human Genome Research Institute. They are also awarding a small amount of grants that total to about $3.75 million. While these values are small, the emerging interest in epigenetics will lead to greater funding in the future (Citation 35).
Major innovators are currently designing the first epigenetic drugs and tools to put on the market. However, it will be tough for companies to reach out to the public while epigenetics is still in its infancy. Zolinza, or Vorinostat, was recently released by Merck. It is one of the first epigenetic drugs to reach the market. With all its groundbreaking, however, Zolinza still poses many problems. According to the drug's own website, "not all patients respond to Zolinza." Zolinza also poses many other side effects, with nearly 50% of patients experiencing diarrhea, fatigue and nausea. During Phase II trials, "9% of patients discontinued treatment because of toxicity" (Citation 1). However, despite the fact that Zolinza is not a "superdrug," the Red Book notes its wholesale price at $8,640 per month (Citation 1). Adjusted for cost-efficiency, Zolinza costs about $30,000 per month (Citation 1), which, even with insurance coverage, is far out of the median household income of $50,503 (Citation 22). With such high prices for epigenetic drugs, consumers may have to wait for some time in order to be able to afford epigenetic pharmaceuticals.
Political Issues
Epigenetics also poses many political issues. While many people will benefit from its advances, others may be vehemently opposed to epigenetics because of its ethical implications. With the potential amount of information that could be released about an individual, privacy issues will certainly come into play as epigenetics makes its way into the mainstream. The current privacy laws of genetics do not cover epigenetic data. In addition, with the digitization of medical records, the potential for information to be lost or stolen will increase significantly (Citation 30). Lawmakers and voters will certainly have to deal with the political problems of epigenetics in the future. In addition, the two main parties in the United States today, the Democrats and the Republicans, already struggle to agree on most scientific scenarios. Genetics and government funding for and regulation of it are a topic of debate today, so as epigenetics gains prominence, it too will become involved in the debate.
