Small and Mighty How microRNA can solve big problems
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onsider for a moment the scale of the perpetual task faced by every organism - controlling gene expression. To pick only the right genes, to be expressed at the right time, in the right place, in the right quantities is no mean feat. Failure at any part of this task could result in disease or death. MicroRNAs (miRNAs) are essential to this process. As their name suggests, miRNAs are tiny, even in relation to the microscopic cellular environment. Typically just 22 nucleotide bases long, they influence genes over 1,000 times
The first miRNA was discovered 20 years ago in the microscopic worm, Caenorhabditis elegans. Since then there has been an explosion of structural and functional knowledge, with miRNAs found in most organisms, from flowers to flies to fish. In the human genome, many regions originally thought to be ‘junk DNA’, actually encode functional and often indispensable miRNA molecules. To date, over 1,500 human miRNA genes have been identified, estimated to collectively govern a staggering 30% of our genes.
o date, over 1,500 human miRNA genes have “Tgovern been identified, estimated to collectively a staggering 30% of our genes” longer than themselves. Proving that size isn’t everything, they may be key to revolutionising the way in which diseases are diagnosed and treated. RNA molecules come in a variety of shapes and sizes and can carry out diverse roles in the cell. Similar to DNA, RNA consists of nucleotides, so can carry genetic information as a special code. Unlike DNA however, miRNAs are non-coding, and instead dynamically regulate our complex genome. They control which genes are expressed by targeting specific coding messenger RNAs to be destroyed, or by inhibiting the translation of these into protein. The central dogma of biology dictates that the manufacture of proteins requires the transmission of a code contained within DNA molecules from the cell nucleus to the main body of the cell, via messenger RNA molecules. The messenger RNA acts as the middle-man, carrying the precious code to the ribosome, the machinery responsible for translating the code, allowing the resulting protein to be synthesised. Challenging this dogma, miRNAs are a spanner in the works, interfering with the flow of genetic information, and effectively silencing genes by shooting their messenger RNA.
Each miRNA efficiently coordinates numerous cellular pathways, by negatively regulating the expression of up to hundreds of genes. This empowers miRNAs to perform a plethora of roles in cell differentiation, proliferation, development, metabolism, and programmed cell
death. But with great power comes great responsibility: such is the magnitude of miRNA’s role in cellular function, that aberrant miRNA expression or behaviour can contribute to a myriad of illnesses, such as diabetes, cancer, and neurological and cardiovascular disease. So how can our expanding knowledge of miRNAs help to treat these diseases? As diagnostic tools they can provide a wealth of information, and drugs can be designed to shackle harmful miRNAs or to mimic the effects of beneficial miRNAs. Given that the expression of certain miRNAs increases or decreases in many diseases, they can act as biomarkers, giving a measurable indicator of a disease state. Studying the differences between the miRNA profiles of healthy and affected tissues allows disease biomarkers to be identified, providing valuable knowledge which can be harnessed to predict the course of a disease in patients. miRNAs are linked
DNA Replication
Transcription
miRNA
RNA
Translation
RISC
How does miRNA regulate gene expression?
Protein
DNA makes messenger RNA, which is then translated into protein. miRNA is incorporated into a large protein complex called the RNA-induced silencing complex (RISC). This complex then supresses the expression of specific target messenger RNAs, either by causing the destruction of the messenger RNA, or by inhibiting its translation into protein.
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