Progress Update: Molecular Mechanism of p38 Kinase-mediated inhibition of DUX4

Posted by Friends of FSH Research on Sep 11, 2021

Update provided by Dr. Vangipurapu
See grant Molecular Mechanism of p38 Kinase-mediated inhibition of DUX4 Gene in Facioscapulohumeral Muscular Dystrophy

The cellular mechanisms that turn on DUX4 in FSHD are poorly understood. A more detailed description of how the DUX4 gene is turned on is essential to identify drug targets for suppressing DUX4. We and others have shown that inhibition of p38 MAP kinase (p38) effectively suppresses myotoxic DUX expression in differentiating FSHD muscle cells in cell culture and in a mouse model of FSHD. We have used CRISPR technology to knock out p38 in FSHD myoblast cell lines in order to understand the contribution of p38 to DUX4 expression. We observed that p38 acts as a driver for DUX4 expression during early myogenesis; however, we also observe p38-independent DUX4 expression during late myogenesis. We are currently identifying transcription factors that promote DUX4 expression in both p38-dependent and -independent manners. Identifying the transcription factors that promote DUX4 expression may lead to better therapeutic targets for FSHD.

Grant Co-Funding: The Chris Carrino Foundation for FSHD