All cells in our body contain the same genetic program, a long sequence of DNA that, in its entirety, is referred to as the genome. DNA, deoxyribonucleic acid, is a molecule comprised of a string of subunits called nucleic acids (four in total). These four nucleic acids are joined together in a multitude of different orders or “sequences” to encode fundamental instructions that direct cell form and function. The genome can be broken down into small functional units, called genes, that are each involved in directing a particular job in the cell. Depending on what a cell needs to do, different genes are expressed (“turned on”) or silenced (“turned off”).
If every cell in an organism has the same genetic program, how can there be so many different types of cells in one body? The answer lies in the fact that not all genes are turned on or expressed in every cell. Determining which genes are turned on and off is critical for generating the diverse types of cells found in the body. Different types of cells express different genes. How does a cell control which parts of the genome are read and which are ignored? One way this can happen is through epigenetic modifications, changes to our genetic information that don’t involve changes in the DNA sequence. The growing field of epigenetics explores how cells use non-sequence changes to exert control over the way the genome is interpreted, as well as how these changes are passed on from one generation to the next [1, 6].
One way that different cells can turn genes on and off is by making modifications to the nucleic acids that comprise a particular DNA sequence. These modifications are referred to as epigenetic signals (literally meaning “above genetic”), and are characterized by two main features. First, such signals or modifications do not change the underlying sequence of nucleic acids (as mentioned previously, the genome stays the same in each cell). Second, these modifications can be passed from one cell to the next generation of cells, thereby conserving which genes are turned on and off in particular cell types. While many types of epigenetic signals exist in the cell , this article will deal primarily with two types of modifications that influence how our genes are turned on and off: DNA methylation and histone modification.
Types of epigenetic signals
One of the best studied epigenetic signals is DNA methylation. This most commonly involves the attachment of a molecule called a “methyl group” to cytosine, one of the four types of nucleic acids making up our DNA genome. When methyl groups are attached to the DNA in genes, these genes are usually turned off or silenced. When a cell divides, its DNA is copied and equally divided among its two daughter cells. During this process, the pattern of DNA methylation can also be copied onto the new DNA, allowing the information determining whether a gene is “on” or “off” to be passed on to the two new cells .
Another type of epigenetic signal, histone modification, involves attachment of various types of molecules to histones, the proteins around which DNA is wrapped. Wrapping DNA around histones allows the genome to be packaged in a much smaller space than if it were left as bare DNA. This tight packing of the genome also tends to prevent genes from being expressed. It is thought that histone modification alters the extent of packing, allowing expressed genes to be less tightly packaged and silenced genes to be more tightly wrapped around histones. Compared to DNA methylation, a wider variety of molecules can be attached to many different locations on histones. This leads to different combinations of modifications that can either help turn off genes or make it easier to keep them on. While defined as an epigenetic change to the genome, scientists still do not know for sure whether histone modifications are truly passed down from one cell generation to the next .
All these different kinds of epigenetic modifications are not independent of each other, but instead act in combination to achieve a synergistic effect on gene expression. For example, certain histone modifications leading to gene silencing have been shown to stimulate DNA methylation in the same region, stably reinforcing the silencing .
Figure 1. Summary of several mechanisms of epigenetic changes in the genome. Epigenetic modifications, like DNA methylation and histone modification, are influenced by a number of environmental factors. Misregulation of these epigenetic signals can possibly lead to various human diseases. (Source: NIH Common Fund)
Epigenetic therapy for human disease
Certain human diseases, such as cancer, often occur due to misregulation of gene expression. This misregulation is often due to changes in the genome sequence, called mutations, which can alter the production or activity of the products of the mutated genes. Abnormal gene expression in disease can also be traced to defects in epigenetic patterning. For example, increased DNA methylation can shut off a gene that would otherwise prevent cancerous cell growth, thereby allowing cells to become cancerous. Given the control that epigenetic marks have on gene expression, drugs that alter patterns of epigenetic marks provide a promising avenue for novel therapies for human diseases, such as cancer and neurological disorders . For example, these drugs could provide an alternative route to treat cancer; instead of destroying cancerous cells, it may be possible to “reprogram” the cells back to a normal state through epigenetic modification .
Rett syndrome was one of the earliest disorders linked to defects in epigenetic modification. Rett syndrome is a neurological disorder affecting young girls and is characterized by excessive hand-wringing, anxiety, seizures, and a number of other symptoms. This disorder was shown to be linked to defects in MeCP2, a protein that attaches to methylated DNA and can consequently alter expression of neuronal genes. Studies in mice show that restoration of normal MeCP2 function in mice lacking this protein can reverse neurological defects. This suggests that these mice do not have permanent neuron damage, indicating that the neurological defects caused by loss of MeCP2 function can be reversed to some degree. These findings show that it may be possible to use drug treatments to compensate for defective MeCP2 function in patients with Rett syndrome .
A recent study  led by Dr. Charles Rudin at Johns Hopkins University examined a new therapy for non-small cell lung cancer using a combination of two drugs, azacitidine and entinostat, that alter epigenetic marks in the genome. Azacitidine interferes with DNA methylation, reducing the extent of gene silencing in the cell, while entinostat belongs to a class of drugs known as histone deacetylase (HDAC) inhibitors. HDAC inhibitors prevent the removal of a type of histone modification that activates genes, thus allowing active genes to remain turned on. By treating patients with low doses of these drugs to minimize their effects on healthy cells, the researchers were able to modify the epigenetic marks in cancerous cells and presumably reactivate genes involved in limiting abnormal cell growth. Although the therapy led to a comparatively small increase in life expectancy for most of the treated patients, the condition of one patient dramatically improved and he remains alive two and a half years after treatment [4, 5]. This study is one of many that show encouraging results concerning the effectiveness of epigenetic therapy . Although epigenetic modification adds an additional layer of complexity to understanding gene expression, this complexity provides fertile ground for identifying treatments for human disease.
Chris Davis is a PhD student in the Biological and Biomedical Sciences program at Harvard Medical School.
Links of Interest
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 Chahrour, M. and H. Y. Zoghbi (2007). “The Story of Rett Syndrome: From Clinic to Neurobiology.” Neuron 56(3): 422-437.
 Egger, G., G. Liang, et al. (2004). “Epigenetics in human disease and prospects for epigenetic therapy.” Nature 429(6990): 457-463.
 Jocelyn Kaiser, ScienceNOW. “Unmuffled Genes Slow Down Lung Cancer.” (2011). <http://news.sciencemag.org/sciencenow/2011/11/unmuffled-genes-slow-down-lung-c.html>
 Juergens, R. A., J. Wrangle, et al. (2011). “Combination Epigenetic Therapy Has Efficacy in Patients with Refractory Advanced Non–Small Cell Lung Cancer.” Cancer Discovery.
 “What is epigenetics?” <http://www.genome.gov/27532724>
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