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

Posted by Friends of FSH Research on Apr 20, 2021

Report by Dr. Rajanikanth Vangipurapu
See grant Molecular Mechanism of p38 Kinase-mediated inhibition of DUX4 Gene in FSHD

We have been studying the role of p38 MAP kinases in regulating DUX4 expression. This work is important to understand the therapeutic potential of p38 inhibitors for FSHD, interpret clinical biomarker results and discover novel drug targets. Our previous work suggested that two or more p38 kinase substrates are involved in promoting DUX4 expression in a p38- dependent manner. We have used CRISPR technology to knock out two candidate transcription factors (p38 substrates) as well as p38alpha and p38beta kinase isoforms in FSHD myoblasts. Our results demonstrate that one of the transcription factors is important for promoting DUX4 expression and experiments are ongoing to link the activity of this factor to p38. Additionally, our data shows that in p38 knockout myoblasts there is a low level of expression of DUX4 that is not dramatically increased upon myogenic differentiation. This is distinct from the situation in non-knockout FSHD cells in which myogenic differentiation promotes large increases in DUX4 expression. This data suggests that p38 mediates differentiation-induced increases in DUX4 expression. Finally, we have begun experiments to map chromosomal regions that mediate p38 effects on DUX4 transcription.