The inventory of the universe is composed of matter, which is located in stars and galaxies. Only a small fraction of the universe is considered ordinary matter (about 5 %); most of the universe is actually made of a mysterious force called dark matter (about 95%). In some ways, a human being is a small universe. The human body has some similarities with the macro-universe in terms of genetic components. A tiny portion of the human genome (the full set of genes and genetic sequences) contains genes that are functional and code for proteins, but a majority of the DNA is made of non-coding DNA. Initially, this led to more than 95% of the human genome being defined as junk DNA. Yet recent findings have shown that this 'junk’ has various purposes. It can function as a spacer element for DNA binding proteins, function as a regulatory element, or be home for non-coding RNAs. Ribosomal RNAs, transfer RNAs, and microRNAs are among the most important non-coding RNAs. While it’s fascination to think about the discoveries made at the cell level regarding DNA, RNA, and proteins, the most fascinating breakthroughs have been at the micro level, among microRNAs. These non-coding RNAs are not translated into proteins, like other coding RNAs, but these tiny RNAs seem to regulate macro systems in the human body, through a hidden layer of regulation that we were not previously aware of.
MicroRNAs as tiny regulators with big roles
Tiny RNAs, known as microRNAs, have been shown to regulate many components of the body’s cellular machinery. They are called microRNAs because they are only 22 nucleotides in size (compared to the 2200 nucleotide-long messenger RNA). Amazingly, these small non-coding RNAs can turn off the translation of their target genes. They act as control switches by targeting the 3' untranslated regions of messenger RNAs (mRNA) for translational repression or cleavage, thus resulting in a reduction of protein levels. Because each microRNAs can regulate hundreds of messenger RNAs, there are probably few cellular processes not affected by microRNAs. For instance, microRNAs have recently emerged as playing important roles in a variety of cellular processes, such as heart development, stem cells, insulin secretion, and cholesterol synthesis. MicroRNAs were first discovered in worms more than 20 years ago. For many years, scientists thought that DNA was transcribed to RNA, and then translated to protein. Those proteins are major regulators in the cell. Now, they appreciate that there are more levels of control and a number of non-coding RNAs that regulate the level of cellular components. About one thousand microRNA genes have been discovered in the human genome. This makes the microRNAs one of the most abundant classes of regulatory genes. As a result of the discovery of this new and major level of regulation in the cell, Dr. Andrew Z. Fire and Dr. Craig C. Mello were awarded the 2006 Nobel Prize in Physiology or Medicine.
Unlike other RNAs, the production of microRNAs is quite different. As depicted in figure 1, the generation and activity of microRNAs requires special microprocessors, known as RNA polymerase II, Drosha, Exportin, Dicer, and RISC complex. RNA polymerase II transcribes (reads the microRNA DNA code) primary microRNA transcripts; then the Drosha process transforms primary microRNA into precursor microRNA in the nucleus. For activity and further processing, precursor microRNA are exported into cytoplasm by Exportin. In the cytoplasm, Dicer cuts precursor microRNA and generates mature 22 nucleotide long microRNA. Then, mature microRNA are incorporated into the RNA inducible silencing complex (RISC) where they target messenger RNAs (mRNA), either for degradation or translational repression. Even though there are extensive studies on microRNAs, it is still mostly unknown how microRNAs target specificity is determined and how they target messenger RNAs for mRNA degradation or translational repression. For a functional microRNA in the cell, it is amazing that a series of microprocessors should take place. They recognize different microRNAs as substrates and do their job as they are supposed to. It seems that the existence and regulation of microRNA processing abilities cannot be by mere chance.
MicroRNAs as therapeutics
MicroRNAs are considered "fine tuners" of cellular processes because of their subtle effects on their targets. However, because microRNAs can target a number of genes and genetic pathways, the study of microRNAs and their regulation and role in diseases is highly promising in terms of developing new therapeutic approaches. Treatments by targeting microRNAs using microRNA inhibitors (antisense RNA nucleotides) are under intense study and several of them have been shown to be effective in animal models. A MicroRNA known as miR-122, for instance, has been shown to regulate cholesterol levels. Scientists targeted this liver-specific microRNA by using a microRNA inhibitor and they found that the downregulation of miR-122 resulted in a 40% decrease in cholesterol levels in the blood.
MicroRNAs in cancer therapy
With the discovery of new and better tools to detect and manipulate microRNA levels in cell cultures and tissues, researchers are now attempting to identify the specific features of each microRNA and their role in cancer and other devastating diseases. There are some microRNAs that are highly correlated with cancer formation. Cancer is cellular anarchy characterized by a proliferation of cells without control. A group of miRNAs known as the miR-17-92 family have been found to increase, and their higher levels result in cancer formation as found in some lymphomas and solid tumors. It is believed that better understanding and use of microRNAs or microRNA inhibitors could enable doctors to treat diseases like cancer. In the near future, microRNA studies are also expected to provide early detection of progressive diseases, better markers for cancer initiation, and cancer specific drug selections.
MicroRNAs as cancer drug boosters
The most straightforward application of microRNA research has been cancer chemotherapies. The potential of use of microRNA applications to increase the effectiveness of current cancer drugs seems highly likely. Companies and universities are looking for microRNA partners to increase the effects of drugs like Taxol, which is currently used in chemotherapy. Taxol, for example, currently works for about 30% of lung cancer patients. But, if we can find a microRNA partner with that drug to make it 40%, it will mean saving thousands of lives. This is a hopeful sign for the future of cancer treatment. On the other hand, it is known that in the case of any chemotherapy, there are unwanted side effects. Although use of higher dose of drug will kill more tumors, the side effects of this drug will cause other issues. Discovery of partners like microRNAs that boost the effectiveness of cancer drugs or decrease side effects can help to treat more patients or help them overcome unwanted side effects.
Taking microRNAs to the heart of the matter
Heart diseases represent the primary cause of death in developed countries. Recent studies have identified microRNAs associated with heart diseases, including cardiac hypertrophy, heart failure (inability of the heart to pump sufficient blood to the organism), and myocardial infarction (the death of the cardiac muscle resulting from interruption of the blood supply). Mir-1 expression levels, for example, are low in human heart disease and it is known to regulate Hand2, a protein required for the growth of heart muscle cells. The levels of another microRNA, called miR-21, have consistently increased through cardiac stress and have been shown to regulate cardiac growth as well. Importantly, miR-133 is believed to repress cardiac hypertrophy, thus the use of synthetic miR-133 molecules is possible as a therapeutic for patients with pathological hypertrophy. However, more studies to understand heart-associated miRNAs are needed in order to have clinical trials for the treatment of heart diseases.
Figure 2. MicroRNAs in the heart. Recent studies have identified microRNAs that are associated with heart diseases, including arrhythmic heartbeat (Arrhythmias), cardiac hypertrophy (enlarged heart), septation defect, and cardiac muscle overgrowth (myocyte hyperplasia).
Micromanaging insulin secretion
MicroRNAs are also associated with the onset of diabetes. Diabetes affects about 23.6 million people in the United States. It can lead to serious health issues and even early death. Diabetes is marked by high levels of blood glucose (also called blood sugar). Complications of the disease are due to defects in insulin production and insulin action. Insulin is among the major regulators of sugar levels in the blood. The human genome contains a number of microRNA genes, whose functions are only beginning to come to light. One such microRNA, miR-375, is already implicated in the secretion of insulin from pancreatic cells, thus it represents a novel pharmacological target for the treatment of diabetes.
The mentioned cases above are examples of the tiny RNAs which regulate cellular processes. The loss of the control in such a small component of the cellular machinery can lead to serious problems, like cancer. To use a metaphor, the regular and healthy government of a state does not allow for the presence of multiple governors. Similarly, regulatory tiny RNAs require a controller who knows how the human body works at the macro and micro levels. This forces us to consider that whomever is controlling the human body must be all sustaining and all knowing. With each new scientific breakthrough, the wisdom of creation becomes more and more apparent. The field of miRNAs is a young research area. New discoveries about microRNAs have brought us new hopes for novel therapies to human diseases. However, future discoveries are required before these therapies can be used in a clinical setting.
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- Average mRNA length: B. Lewin, Genes 5, Table 2-2. Oxford University Press.
- MicroRNA biogenesis figure: http://content.nejm.org/content/vol359/issue25/images/large/14f1.jpeg