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Senior Member
Join Date: Aug 2006
Location: Pennsylvania
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Identical twins not as identical as believed
Researchers discovered that chromatin, the complex formed by DNA and histones (proteins that bind strongly to DNA, thereby packaging it in chromosomes) regulate gene expression. This additional layer of regulatory instructions, which are not held in DNA, comprise the epigenetic code.
Epigenetic differences explain why two cloned organisms are not the same or why twins develop illnesses of distinct genetic origin. Epigenics not only adds to our understanding of the relations between the environment and genetics but also provides an explanation of the basic aspects of cell biology. Deciphering and understanding the epigenome will shed light on fundamental processes in cell physiology.
This knowledge will improve our understanding of the development of tumors and other diseases, and may lead to the design of new treatments for these conditions. A new family of epigenetic drugs, designed to reverse the changes in the epigenome that occur during the development of several kinds of cancer, is currently available. Several of these pharmacological agents are now being used to treat some types of leukemia and breast cancer.
Scientists have shown how the occurrence of cancer is repressed epigenetically by modifying not the DNA code of a gene, but the spool-like histone proteins around which DNA tightly wraps itself in the nucleus of cells in the body. By studying how and when these histone changes occur, scientists can explain human diseases that can't be readily attributed only to irregular genes.
Regulation of gene expression is not entirely determined by information contained within the DNA sequence, but this gene regulatory information is also stored on the histones around which DNA wraps itself. Together, DNA and histones form a package called chromatin, which makes up chromosomes.
Chromatin stretches open to allow the cell's molecular machines to have access to DNA and thereby to switch on genes. However, when chromatin is closed, the same gene-activating machinery cannot penetrate the protective barrier, and gene expression cannot occur. Chemical changes to tail-like structures of histones can open or close chromatin, thus regulating gene expression.
The "on" and "off" dynamics of histone modifications are important for the regulation of gene expression and that misregulation of these modifications can lead to disease.
DNA and genetic information
Evolution is about information. The genetic information contained within a human cell consists of two very similar but non-identical sets of information, joined at the time of fertilization and conception. The information specifies details for the production and regulation of the machinery of life. This information is largely redundant as copies are received from each parent.
The information storage system, the "hard drive" of cells that holds the information needed for cell replication and survival, is made of DNA and proteins. The primary storage medium is DNA. Digital information is stored in duplicate in the sequences of bases that make up the famous double stranded helix of DNA. Each strand of the double helix contains the same information but in a complementary or mirror image. This provides a "back-up" copy of the data. When cells divide, the DNA strands separate. The individual strands then serve as templates for the synthesis of a new strand of DNA. In the process, the double helical structure of DNA is restored and each cell receives one set.
The DNA of a normal human cell has approximately 6 billion base pairs divided into 46 double-stranded chains called chromosomes. The DNA strands in chromosomes are folded and coiled around themselves. In normal human cells, there are 22 pairs of chromosomes and two sex chromosomes. Half of the chromosomes are inherited from each parent.
DNA is like a long chain made of four different colored beads. Different sequences of the beads (bases) specify different information. The information is contained within the sequence. The bases that make up DNA are composed of four different chemical structures, Adenine (A), Thymine (T), Cytidine (C), and Guanine (G). These are like the colors of the beads. The double helix of DNA has two strands of DNA that bind together in a complementary fasion. A bind to T and G binds to C. To understand how the sequence of bases or beads contains information, consider the analogy to letters and words. Individual letters do not have meaning. However, sequences of letters that form words have meaning. The information is in the sequence or pattern. By a complicated series of biochemical processes, the information contained in the DNA base sequences is converted into RNA, proteins and the machinery of life.
Epigenetic Information
DNA is the major information storage system of cells, but there are others. Information stored outside of the DNA sequences is called epigenetic. Epigenetic information can reside in proteins that regulate the expression of the information within DNA. Epigenetic information can also be encoded by minor chemical modifications of the DNA bases and of such proteins as histones. The addition of methyl groups (base methylation) can turn off or deny access to the information within parts of the DNA.
The importance of epigenetic information is illustrated by Dolly the cloned sheep. A nucleus containing the DNA from a skin cell was transplanted into an ovum lacking a cell nucleus, and then implanted into a sheep uterus. The resulting newborn sheep was genetically identical to the adult donor of the nucleus. The cloning process reset the epigenetic information of the adult skin cell. Similar experiments have been done using mouse melanoma cells. Amazingly, the cancer cells grew into mice. Ultimately, the resulting mice developed melanomas and other cancers. Differences in epigenetic information can also produce differences between genetically identical twins. Although, identical twins have identical DNA, their epigenetic information can differ and produce different traits.
Mutations and genetic alterations
From time to time, computer files become corrupted. Data is lost or modified. The same occurs in the genetic and epigenetic information of cells. The causes are innumerable. Molecules rapidly bounce around. There is background radiation from cosmic rays and natural decay of radioactive elements such as potassium 40. Reactive free radicals are constantly being produced. Toxic and mutagenic chemicals naturally abound in the environment. There are always thermodynamic and statistical fluctuations.
It is inevitable that cellular information becomes damaged or altered during storage and replication. Oxygen alone is estimated to damage about ten thousand DNA bases per cell per day. Normal cell division is accompanied by the formation of about 50 double stranded DNA breaks per cell. Cells have evolved extensive but imperfect repair mechanisms to correct DNA damage. Since DNA is double stranded there is a backup copy of the required information to facilitate repair. Nonetheless, with time irreversible information loss and corruption does occur. This results in genetic variation between cells, a pre-condition for evolution.
The level of data corruption is increased by agents that damage DNA. Examples include cigarette smoke, radium, sunlight, X-rays and anticancer drugs. One of the most potent examples of DNA-damaging agents was found in natural health food products used for weight reduction. They included Chinese herbs containing aristolochic acids, a class of chemicals that bind tightly to DNA. In the late 1990's, an epidemic of cancer of the kidney and urinary tract resulted. This should cause one to question the widely held notion about the safety and superiority of "natural" remedies.
There are numerous natural chemicals present in food that very efficiently damage DNA and are carcinogenic, such as aflatoxins and Ochratoxin A. Cooking food, especially meats, generates mutagenic and carcinogenic compounds. Common viral infections can also damage DNA, not just cancer-causing viruses like papillomavirus, but also ordinary viruses. Viral and non-viral DNA can become incorporated into the cellular DNA and alter the information content of cells.
Agents that interfere with the proper transfer of information to each cell at the time of division cause profound alterations in the information content of cells. Such agents can cause the chromoosomes to be unevenly distributed during cell division. The DNA itself, at least initially, is not damaged, but the net result is an abnormal number of chromosomes in the cell, or a condition called aneuploidy. This can trigger genetic instability and lead to the acquisition of other genetic alterations. Aneuploidy is a change in the number of chromosomes that can lead to a chromosomal disorder. Aneuploidy is common in cancerous cells.
Literature Citation:
Ting AH, et all., The cancer epigenome, components and functional correlates. Genes Dev. 2006 Dec 1;20(23):3215-31
Szyf M., Targeting DNA methylation in cancer. Bull Cancer. 2006 Sep 1;93(9):961-72
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