During development, many crucial genes help organisms form properly. One of those genes is myogenic determination gene number 1 (MyoD), which can exert a powerful influence as a “genome organizer." It can attach to DNA to help control the development of muscles, and can also help repair muscles that have been injured or damaged. MyoD can reprogram stem cells so they will build more muscle. Now scientists have found that this crucial gene can not only trigger the expression of genes, it can also turn off gene expression. The findings have been reported in Genes & Development.
In this study, the researchers analyzed how MyoD worked to reprogram fibroblasts into skeletal muscle cells and in a mouse model of muscle injury. The researchers observed MyoD binding to expected places in the genome, where it can activate the expression of other genes. These sites are known as myogenic E-box motifs. But there were many other binding events in places that were not expected; these happened to also decrease the expression of genes. MyoD was binding to places other than just the E-box motifs, challenging current assumptions.
The research also showed that MyoD was reducing the expression of genes that were related to cell growth and proliferation, and alternate cell lineages. Since the genes that a cell expresses can determine its function and type, this confirms that MyoD has a powerful influence on cell identity and reprogramming.
The investigators also noted that this study has shown that one regulator of gene transcription can function as a repressor, and is expanding what we know about transcription factors and the control of gene expression.
"Transcription factors are way more versatile than we thought, and this newfound versatility is dictated by where and how they bind to DNA,” said senior study author Pier Lorenzo Puri, MD, professor at Sanford Burnham Prebys.
It may also be possible to leverage this knowledge to gain new insights into regenerative therapeutics.
"In regenerative medicine, we hope to treat certain medical conditions by turning one cell type into another, one pathological cell into one physiologically normal or even therapeutic cell," said Puri.
To turn one cell type into another type of cell, it is not only important for a cell to activate the right genes; but a cell also has to turn off the genes it was expressing to make that change.
The researchers want to learn more about the consequences when the previous identity of a cell is not totally repressed, and if this can help explain variations in muscle recovery after injury, or age-related muscle decline.
"It may be that small alterations in MyoD's silencing role are tolerated by the body but progressively impair muscle function," said Puri. "Better understanding this concept may have an enormous impact in terms of biomedical applications for regenerative and sports medicine for athletes and sarcopenia patients."
Sources: Sanford Burnham Prebys, Genes & Development
