Sergio Pistoi, Science Writer and Consultant

Epigenetics explains why the “junk” DNA in our genome is not so junk after all.

Unpublished

If the genome is, with a fair approximation, the cookbook with the recipes for all the components that make up our organism, researchers are finally able to browse the entire book and even to recognize single phrases and chapters - genes and chromosomes, respectively. At least, this was the good news that came with the publication of the final draft of the human genome. The bad news (or not, depending on your point of view) is that, when it comes to understand how the genome works, the DNA sequence is only part of the story.

The genome draft has showed that humans have between 25.000 and 40.000 genes, only about three times as much as the fruit fly and almost as much as the thale cress, a small plant, simpler organisms that, as far as we know, are not able to write or send spacecrafts to the moon. It is now clear that what makes the difference between Einstein and a banana is not the number of genes but their type and probably, the way they are regulated. Moreover, 95 per cent of our DNA does not code for any protein, and it’s hard to think that all this information, which every cell painstakingly passes over to its descent, is just “junk”- as it was dubbed in the past. Indeed, in recent years researchers have found that the genome has a layer of complexity bigger than just the sequence of letters contained in the genes.

They called this type of regulation epi-genetic ( literally, “sitting above the genes” ) because it does not affect the content of genes but, instead, decides if and how they will be switched on, read by the cellular machinery and eventually traduced into proteins. This brings an enormous level of complexity to the genome: each gene has a unique DNA sequence but can have potentially infinite epigenetic states.

Scientists are accumulating evidence that epigenetic phenomena play a critical role in normal growth, functioning and aging of the organisms. Faulty epigenetic mechanism are also suspected of contributing to a variety of diseases. The Online Mendelian Inheritance in Man (OMIM), a database of human genes and genetic disorders, lists more than a hundred ailments where epigenetic mechanisms are involved or strongly suspected. Some are rare, such as the Facio-Scapulo-Humeral muscular dystrophy, the Prader-Willi, Angelman and Beckwith-Wiedemann Syndromes, but the list also includes common diseases such as cancer and diabetes. By looking at the “dark face” of the genome, the study of epigenetics could suggest new strategies to treat these disorders.

There are several known epigenetic mechanisms, and many other are probably to be discovered. Methylation, a chemical modification by which an hydrogen atom is replaced by a small carbon compound called methyl, is a well studied mechanism that cells use to earmark portion of the genome: when methyl groups are added to a gene, this usually means “this gene is locked up”. It is a bit like stapling or gluing together the pages of a book: the information itself, stored in the print or in the DNA, is unaffected, but has become impossible to access. RNA, a working copy of the DNA that transfers genetic information in the cell like a computer diskette, is emerging as another fascinating actor of epigenetics. Antisense RNAs (anti-copies of genes that can block their information) and non-coding RNAs - both thought once to be useless- have been instead found to regulate the activity of thousands of genes and even of entire chromosomes.

A sophisticated mixture of methylation and RNA-mediated “silencing” is responsible for blocking one of the two X chromosomes of females. Epigenetics also explains a genetic phenomenon called imprinting, where a trait becomes apparent if it is inherited from the mother and not from the father, or vice versa. For example, the Angelman syndrome, a rare genetic disease caused by the loss of a portion of chromosome 15, will manifest only if the defective chromosome comes from the mother. The same defect, but on the paternal chromosome, will curiously cause a different disease, the Prader Willi syndrome. Researchers have found evidence that this happens because the maternal and paternal versions of chromosome 15 are imprinted in different ways. Epigenetic defects also contribute to the genetic chaos that leads to cancer. In fact, some experiments suggest that methyl-removing drugs could be useful to treat a form of leukemia and maybe other types of cancer, in which tumor-suppressor genes are blocked by methylation.

Stem cell research and cloning could benefit largely from advances in epigenetics, too. Imprinting has an amazing capacity to wipe out and restore itself during development: soon after an oocytes is fertilized, nearly all imprinting is removed from the chromosomes but is then re-established during gestation. Researchers agree that most clones obtained in the laboratory fail to develop properly because they miss this important, and still mysterious, “reprogramming” step. Adult stem cells, too, must go trough a similar reprogramming process before they can transform themselves into different types of tissues and be used in therapy.

The exploration of the heretofore invisible side of the genome has just begun. One day, the consequences for the understanding of our biology and for our health could be huge.

Copyright Sergio Pistoi  All rights reserved