Saturday, September 7, 2024
9/7/2024
PROJECT SUMMARY Facioscapulohumeral muscular dystrophy (FSHD) is a devastating muscle disease caused by the inappropriate expression of an early embryonic transcription factor, DUX4, in the skeletal muscle. DUX4 activates hundreds of genes in muscle cells and eventually induces toxicity. Which of the DUX4-driven gene expression changes underlie its pathogenicity is currently unknown. Our previous research has shown that DUX4 significantly affects RNA metabolism in muscle cells. Specifically, DUX4 induces altered splicing and proteasome-mediated loss of RNA quality control, with a resultant increase in aberrant transcripts that encode potentially toxic, truncated proteins. Hence, we hypothesize that DUX4-induced misregulation of RNA metabolism is a key driver of its pathogenicity in FSHD. To test this hypothesis, we seek to determine the mechanistic underpinnings of how DUX4 increases aberrant RNAs in the cell. We will do so by determining the mechanism of DUX4-induced aberrant splicing (Aim 1) and identifying factors that induce loss of RNA quality control via the ubiquitin-proteasome system upon DUX4 expression (Aim 2). We will use a combination of biochemistry, genome engineering, proteomics, and genomics to address these questions in a temporally controlled, inducible DUX4 expression system. Successful completion of these studies will allow us to determine how DUX4, a transcription factor, rewires the post-transcriptional gene regulatory network of muscle cells. Given that perturbed RNA metabolism is a common mechanism underlying many muscle diseases, a better understanding of its role in FSHD could also aid in novel therapeutic discovery.
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