The Epigenetics Revolution

There is a condition in humans called DiGeorge syndrome in which a region of about 3,000,000 bases has been lost from one of the two copies of chromosome 22[161]. This region contains more than 25 genes. It’s probably not surprising that many different organ systems may be affected in patients with this condition, including genito-urinary, cardiovascular and skeletal. Forty per cent of DiGeorge patients suffer seizures and 25 per cent of adults with this condition develop schizophrenia. Mild to moderate mental retardation is also common. Different genes in the 3,000,000 base-pair region probably contribute to different aspects of the disorder. One of the genes is called DGCR8 and the DGCR8 protein is essential for the normal production of miRNAs. Genetically modified mice have been created with just one functional copy of Dgcr8. These mice develop cognitive problems, especially in learning and spatial processing[162]. This supports the idea that miRNA production may be important in neurological function.

We know that ncRNAs are important in the control of cellular pluripotency and cellular differentiation. It’s not much of a leap from that to hypothesise that miRNAs may be important in cancer. Cancer is classically a disease in which cells can keep proliferating. This has parallels with stem cells. Additionally, in cancer, the tumours often look relatively undifferentiated and disorganised under the microscope. This is in contrast to the fully differentiated and well-organised appearance of normal, healthy tissues. There is now a strong body of evidence that ncRNAs play a role in cancer. This role may involve either loss of selected miRNAs or over-expression of other miRNAs, as shown in Figure 10.5.

^{Figure 10.5 Decreased levels of certain types of microRNAs, or increased levels of others, may each ultimately have the same disruptive effect on gene expression. The end result may be increased expression of genes that drive cells into a highly proliferative state, increasing the likelihood of cancer development.}

Chronic lymphocytic leukaemia is the commonest human leukaemia. Approximately 70 per cent of cases of this type of cancer[163] have lost the ncRNAs called miR-15a and miR-16-1. Cancer is a multi-step disease and a lot of things need to go wrong in an individual cell before it becomes cancerous. The fact that so many cases of this type of leukaemia, the most common human leukaemia, lacked these particular miRNAs suggested that loss of these sequences happened early in the development of the disease.

An example of the alternative mechanism – over-expression of miRNAs in cancer – is the case of the miR-17-92 cluster. This cluster is over-expressed in a range of cancers[164]. In fact, a considerable number of reports have now been published on abnormal expression of miRNAs in cancer[165]. In addition, a gene called TARBP2 is mutated in some inherited cancer conditions[166]. The TARBP2 protein is involved in normal processing of miRNAs. This strengthens the case for a role of miRNAs in the initiation and development of certain human cancers.

Hope or hype?

Given the increasing amounts of data suggesting a major role for miRNAs in cancer, it isn’t surprising that scientists began to get excited about the possibilities of using these molecules to treat cancer. The idea would be to replace ‘missing’ miRNAs or to inhibit ones that were over-expressed. The hope was that this could be achieved by dosing cancer patients with the miRNAs, or artificial variants of them. This could also have applications in other diseases where miRNA expression may have become abnormal.

Big pharmaceutical companies are certainly investing heavily in this area. Sanofi-Aventis and GlaxoSmithKline have each formed multi-million dollar collaborations with a company called Regulus Therapeutics in San Diego. They are exploring the development of miRNA replacements or inhibitors, to use in the treatment of diseases ranging from cancer to auto-immune disorders.

There are molecules very like miRNAs called siRNAs (small interfering RNAs). They use much the same processes as miRNA molecules to repress gene expression, especially degradation of mRNA. siRNAs have been used as tools very extensively in research, as they can be administered to cells in culture to switch off a gene for experimental investigations. In 2006, the scientists who first developed this technology, Andrew Fire and Craig Mello, were awarded the Nobel Prize for Physiology or Medicine.