Unravelling the microRNA-chromatin remodelling circuitry that drives myogenesis

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THE 'BIG' PICTURE: Multi-cellular organisms contain many distinct cell types with very specialized functions. For example, we need skeletal muscle to be able to move while our skin prevents dehydration and protects us from injury and infections. Amazingly all these different cells arise from a single cell, the fertilized egg. The development of an embryo begins when the egg starts dividing to give rise to many cells. The cells are initially multi-potent, but they gradually become specialized and restricted to perform specific tasks. This cell-lineage restriction is regulated by factors that influence the activity of genes and regulate the accessibility of the genome in the nucleus of the cell. Some genes are 'off' and DNA is packaged tightly, other regions are more loosely packaged and therefore 'open' and accessible to factors that can switch a gene 'on'. If a gene is 'on', it means the gene will be expressed and actively transcribed. The regulation of gene activity is crucial for cells to become specialised in their functions.THE QUESTION: We are interested in the molecules that control the development of muscle in an embryo. Why do progenitor cells develop into muscle rather than other related cell types, such as fat, cartilage, bone or connective tissue? Our studies focus on a class of RNA molecules, which we found regulate the factors that control the accessibility of the genome. These non-coding RNAs were discovered recently and because they are very small, they were called 'microRNAs' (miRs), they control the translation of genes into protein - a fundamental job required in all cells. WHY IS THIS IMPORTANT? Regulating the accessibility of the genome is very important during cellular differentiation in embryo development. Understanding this genetic programme is also important for muscle regeneration and repair after injury or long-term bed rest. The process of cell lineage determination is also crucial for the differentiation of stem cells, or for the reprogramming of already specialized cells towards a different fate. We know many of the components involved, but we still do not understand in detail how they function, or how they are put together. We recently discovered that microRNAs influence the composition of these 'reprogramming' complexes and we have a well-defined system in which to study this more systematically. This offers the unique opportunity to identify all of the important players and will provide a deeper mechanistic insight at the molecular level. This is needed, not only to fully understand how specialized cells form in developing embryos, but also to be able to use stem cells in regenerative medicine and tissue engineering, emerging fields of increasing importance and with significant future potential for medicine and health. We will learn how an embryo makes normal, healthy, working muscle and this will in the long-term benefit people who suffer from various conditions that affect muscle health or help to alleviate age related muscle-loss.EXPERIMENTAL MODEL SYSTEM: We use very early chick embryos, which are very similar in morphology to early human embryos, to investigate the roles of important microRNAs present in muscle. We will use protocols to identify how they affect the the factors that control the accessibility of the genome in naïve and differentiating muscle cells. We have experience with these state-of-the-art molecular methods in the chick embryo, an accessible experimental system and we have assembled a highly skilled team of researchers to execute this programme of research.