Base editing of DUX4 somatic polyadenylation signal – towards new therapeutics for FSHD

Investigator: Darina Šikrová MSc

Category: Research - Basic

The human genome encodes for approximately 20,000 protein-coding genes and every gene can be thought of as a recipe according to which a cell can produce proteins - the true workhorses of the cell. However, individual cells in our body do not need to produce proteins from all 20,000 genes present in their genome. Every cell type requires a different specialized set of proteins to ensure a proper cell’s performance and therefore, only genes that code for these proteins are turned on in the cell and the rest is switched off. For example, red blood cells need to distribute oxygen throughout our body and therefore need to have a protein apparatus which can bind and release oxygen, whereas muscle cells need to be able to contract and relax after receiving stimuli from neurons and therefore need to be equipped with different proteins to do so and, on the other hand, do not need the protein apparatus for transporting oxygen through the body. In addition, the cellular machinery which is responsible for “reading” the genes and uses what is read for the production of proteins needs to be able to recognize the gene in the genome. Therefore, the beginning and the end of every gene is marked by a special signal (START and STOP signal, respectively), just like the beginning of every sentence in the text is indicated by a capital letter of the first word and its end is marked by a dot after the last word.

Facioscapulohumeral muscular dystrophy is caused by a mis-production of a protein termed DUX4 in skeletal muscle cells due to the incapability of muscle cells to switch the DUX4 gene off. The DUX4 protein then interferes with the proper functioning of the muscle cells which in the end leads to their death. One of the therapeutic options would be to impede with the production of DUX4. As mentioned earlier, for a faithful reading of a gene by the cellular machinery, the gene has to have a recognizable START and STOP signal. With that in mind, we will pursue to modify the STOP signal of the DUX4 gene in a way that it cannot be longer recognized by the reading cellular machinery. Our hypothesis is that such STOP signal modification will lead to inefficient production of DUX4 and ultimately its lower levels in skeletal muscle cells.

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