Wednesday, September 23, 2009


When it comes to inheritance, there's no beating the DNA sequence for storing and passing on complex information. But other, "epigenetic" mechanisms also bequeath information to subsequent cells or offspring, sometimes in response to environmental changes.

In principle, the word "epigenetics" could apply to any inheritance outside of the genetic sequence. For example, when a cell divides, its contents are divided among the daughter cells. Any transcription factors or other chemicals that alter gene expression are therefore passed on independently of the DNA (along with the mitochondria, which have their own DNA). In recent years, however, "epigenetics" has come to be used mainly to describe two types of chemical changes directly associated with DNA in the nucleus, other than its sequence.

These changes modify how active various genes are in a particular cell. They are particularly important for enforcing the "no turning back" feature of differentiation from versatile stem cells to specialized cells, helping to shut off cellular programs that were active in the early embryo. Moreover, epigenetic changes are passed on during cell division, so that the differentiated cells and all cells made from them lose their ability to become other types of cell. It should not be surprising that many cancers subvert the epigenetic programming to help them re-activate embryonic programs to help them survive and spread. Researchers have identified many epigenetic modifications in cancer cells.

Epigenetic changes can also pass between generations. Biologists have long known of cases of "imprinting," in which the mother's or the father's DNA is inactive in the offspring. Even in people, researchers have found that food shortages in Holland at the end of World War II resulted in changes in the metabolism of the children of women conceived during that period. Such effects are unusual, but profound.

This sounds disturbingly like inheritance of acquired characteristics, as in Kipling's "Just-So Stories." This concept, often misleadingly associated with early 1800's evolution pioneer Jean-Baptiste Lamarck, was supplanted by Darwin's notion of natural selection of random variations. But persistently activating or suppressing pre-existing genes for a few generations, even in response to environmental pressures, is not the same thing as creating novel properties. Some scientists, notably Eva Jablonka of Tel Aviv University, maintain that epigenetic effects can be permanently enshrined in the sequence, but that remains a minority view. Equating epigenetics with Lamarckism is misleading, despite having a grain of truth.

The two best known epigenetic mechanisms are chemical changes that alter the transcription of DNA. One mechanism modifies the DNA itself, while the other modifies the packaging of the DNA in the nucleus.

(Click to open in new window. Source: NIH)

In DNA methylation, methyl (-CH3) groups are chemically bonded to a base in the DNA sequence, usually a cytosine (C) next to a guanine (G), together called CpG. The presence of the methyl group suppresses translation of the DNA sequence that contains it. In addition, the cell contains enzymes that recognize methylation of one chain of DNA and methylate the other chain, helping to propagate the information.

The second mechanism affects the packing of the DNA into the compact structure known as chromatin. The paired DNA chains wrap tightly around a cluster of proteins called histones to form a nucleosome. Nucleosomes strung along the DNA chain themselves pack into compact arrangements that make it hard for the transcription machinery to get at them.

The details of this process are only partially understood. One thing that is known is that free "tails" of the histone proteins straggle out of the nucleosomes, and that chemical modifications of these tails modifies transcription. The modifications include single or multiple methylation or acetylation (adding -COCH3) of particular amino acids positions in the tail, as well as binding of other factors. The details matter: particular modifications either increase or decrease transcription.

In recent years researchers have developed techniques for mapping both DNA methylation and chromatin modification over large regions of the genome. Using these techniques and others, biologists are beginning to understand when and where these epigenetic modifications occur in normal and diseased cells, how nutrition and other environmental influences change them, and how specific modifications are actively regulated to modulate gene expression.

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