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When DNA was first described, its role within the cell as a carrier of information, and the process through which this information is read and used to produce proteins, seemed fairly straightforward. One common analogy is of DNA as a cellular blueprint: the means to make any protein the cell may need is just sitting out in the open on a chromosome, waiting to be transcribed.
However, not all genes are quite so easily accessible. Changes in the structure of DNA can lock some genes up and label others with a giant molecular billboard. These changes, which affect DNA structure without changing the sequence of a gene, are referred to as epigenetic alterations.
When all goes right, this focuses the work of proteins involved in transcription, directing them to help make proteins essential for the function of the cell. Since every process in the cell can be disrupted in some way, and many of these disruptions lead to disease, it is not surprising that scientists have discovered a link between some human conditions and errors related to epigenetics. For example, there is a link between epigenetics and skeletal diseases.
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How Epigenetics Works
The double-helix of the DNA molecule does not exist in isolation. In fact, its twists and turns are wrapped around proteins known as histones. The combination of DNA and histones is called chromatin. Changes in the structure of chromatin are capable of making some genes available to be transcribed and keeping others stably locked down.
Typically, the "open" and "closed" states of a set of genes are determined by small chemical markers on the histones. Each of these markers can be placed there or removed by proteins within the cell; a change of state from "open" to "closed," or vice versa, is commonly called chromatin remodeling.
Usually, cells don't undergo much chromatin remodeling in the course of their lives; specific cell types have characteristic patterns of chromatin which are related to their particular function. The job of the proteins which control chromatin is to maintain this mostly steady state. The epigenetic errors which lead to skeletal diseases (among others) are often the result of inherited mutations in these proteins. These mutations cause cells throughout the body to have substantial disruptions in their chromatin structure, seriously affecting the function of their DNA.
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Skeletal Conditions Related to Epigenetics
Schimke immuno-osseous dysplasia, or SIOD, is one example of a link between epigenetics and skeletal diseases. The condition produces effects in many different bodily systems; some of the effects on the skeleton include dysplasia of the spine and the ends of long bones. SIOD is caused by mutations in a gene called SMARCAL1; the protein product of this gene is a regulator of chromatin structure. While it is unclear why mutations in SMARCAL1 cause the specific effects characteristic of SIOD, it makes sense that a protein which can control expression of many genes via chromatin remodeling would cause widespread problems if disrupted.
a-thalassemia X-linked mental retardation, known as ATRX, is similar, in that the disease impacts multiple systems in a somewhat haphazard way, and is caused by a flaw in epigenetic function. In this case, the affected gene was named ATRX because of the associated condition. People suffering from ATRX may have skeletal flaws in facial features, microcephaly (a substantially smaller skull than average), and the inability to walk. Much like SMARCAL1, the protein produced by ATRX is also thought to regulate chromatin structure. Studies in mice have shown that ATRX levels in the cell are very tightly controlled; too much or too little will produce serious flaws in multiple systems of the body. This is completely understandable when considering how improperly structured chromatin can affect many different genes.
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Allis, Jenuwein, and Reinberg, eds. Epigenetics. Chapter 23, "Epigenetics and Human Disease." Cold Spring Harbor Laboratory Press, 2007.