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Gene regulation

Micro by name; mighty in nature

Each individual cell in our body has its own specific set of instructions that allow it to execute a particular task – like ensuring a red blood cell can carry oxygen, and a nerve cell can detect pain. By definition, these sets of instructions must be wildly different between various cell types – but how does the body control which instructions are assigned to each cell? The answer is a very complex set of mechanisms that are exceedingly difficult to understand, but new tools developed by a joint team of scientists from the Weatherall Institute of Molecular Medicine and Department of Physiology Anatomy and Genetics in Oxford, should help decipher one layer of this regulatory landscape. Dr. Bryony Graham explains more.

At the heart of each individual cell in our body lies a central compartment called the nucleus, which holds inside it all the information required to build an entire human being. This incredibly complex set of instructions is encrypted as a code within arguably the most famous of all biological molecules – our DNA.

RNANeedless to say, if every single cell in our body would try to develop at the same time in a complete human being, the consequences would be devastating (although it would no doubt make a great theme for a Sci-Fi movie). Therefore, each cell only reads a small part of the code, and consequently carries out one tiny subset of all the programmes the human body requires to develop and function in perfect harmony. Billions of specialized cells happily carry out their specific tasks all day every day, and they all work together to produce the finished product – your living, breathing self.

But how is this astonishing process regulated? How does each cell only have access to a specific subset of instructions? This question underlies one of the most challenging and fascinating endeavors in molecular biology, encompassing a vast spectrum of components, all of which are incredibly difficult to tease apart. But recent work by a team of scientists from the WIMM and Department of Physiology at the University of Oxford developed a powerful technology platform that will hopefully allow scientists to investigate one dimension of this problem more accurately than ever before.

One mechanism of controlling the set of instructions that a cell follows, is to regulate the number of copies decoded from DNA (the instruction manual) that are available for the cell to read. The scientific name for such decoded messages is messenger RNA (or mRNA for short) and these molecules shuttle between the nucleus and the rest of the cell, carrying the information encoded within the DNA. The levels of mRNA molecules impact every cellular process, and can dramatically affect cell function when they are inadvertently changed – therefore they must be tightly regulated with minute spatial and temporal precision.

This is where microRNAs step in. microRNAs are, well, tiny versions of mRNAs. These miniscule molecules bind to their bigger counterparts and tag them for destruction – pretty powerful stuff for something so small. But until recently working out which microRNAs target which mRNAs has been a daunting task, and scientists have largely had to rely on computational predictions that only get one in every three interactions right, or indirect assays.

Now, a team led by Tudor Fulga have used sophisticated tools for DNA engineering called TALENs and the CRISPR/Cas9 system to work out which microRNAs directly target which mRNAs in a living organism – something which was not feasible before. In addition, they have developed a method to systematically investigate functional microRNA/mRNA interactions in cells in culture in a laboratory environment, which will be invaluable to researchers working on human cells that cannot be investigated in any other way.

These exciting new developments, published in the journal Nature Communications, hold the potential to revolutionize the accuracy with which scientists can predict how mRNA levels are controlled by microRNAs. Changes in the levels of microRNAs themselves are found in a wide range of human diseases, including many types of cancer, so understanding exactly how these tiny molecules work will be critical for the development of effective new therapeutic strategies.

Post edited by Tudor Fulga.

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