From one genome,200 types of cells

How does this assignment process work? The answer,researchers are finding,is that a second layer of information is embedded in the special proteins that package the DNA of the genome. This second layer,known as the epigenome,controls access to the genes,allowing each cell type to activate to its own special genes but blocking off most of the rest. A person has one genome but many epigenomes. And the epigenome is involved not just in defining what genes are accessible in each type of cell,but also in controlling when the accessible genes may be activated.

Since the settings on the epigenome control which genes are on or off,any derangement of its behaviour is likely to have severe effects on the cell. There is much evidence that changes in the epigenome contribute to cancer and other diseases. The epigenome alters with age–identical twins often look and behave a little differently as they grow older because of accumulated changes to their epigenomes. Understanding such changes could help address or retard some of the symptoms of ageing. And the epigenome may hold the key to the dream of regenerative medicine,that of deriving safe and efficient replacement tissues from a patient’s own cells.

The epigenome consists of many million chemical modifications,or marks as they are called,that are made along the length of the chromatin,the material of the chromosomes. The chromatin includes the double-stranded ribbon of DNA and the protein spools around which it is wound. Some of the marks that constitute the epigenome are made directly on the DNA,but most are attached to the short tails that stick out from the protein spools. Marks of a certain kind generally extend through a large region or domain of the DNA that covers one or more genes. They are recognised by chromatin regulator proteins that perform the tasks indicated by each kind of mark.

The basic blueprint for the epigenomes needed by each cell type seems to be inherent in the genome,but the epigenome is then altered by other signals that reach the cell. The epigenome is thus the site where the genome meets the environment.

The organisation of the epigenomes seems to be computed from information inherent in the genome. “Most of the epigenetic landscape is determined by the DNA sequence,” says Bradley Bernstein,a chromatin expert at Massachusetts General Hospital. The human genome contains many regulatory genes whose protein products,known as transcription factors,control the activity of other genes. It also has a subset of master regulatory genes that control the lower-level regulators. The master transcription factors act on each other’s genes in a way that sets up a circuitry. The output of this circuitry shapes the initial cascade of epigenomes that are spun off from the fertilised egg.

The other shapers of the epigenome are the chromatin regulators,protein machines that read the marks on the histone tails. Some extend marks of a given kind throughout a domain. Some bundle the nucleosomes together so as to silence their genes. Others loosen the DNA from the nucleosome spools so as to ease the path of the transcription machinery along a gene.

The ideal of regenerative medicine is to convert a patient’s normal body cells first back into the embryonic state,and then into the specific cells lost to disease. But to prepare such cells safely and effectively,researchers will probably need to learn how to control and manipulate the chromatin of the epigenome as well as the transcription factors that shape cell identity.

Besides governing access to the genome,the epigenome also receives a host of signals from the environment. A family of enzymes called sirtuins monitor the nutritional state of the cell,and one of them removes a specific mark from the chromatin,providing a possible route for the genome to respond to famine conditions. Accumulating errors in the epigenome’s regulation could allow the wrong genes to be expressed,a possible cause of ageing.
_NICHOLAS WADE,NYT