D4Z4 Coding Transcripts and FSHD

PROJECT SUMMARY Facioscapulohumeral dystrophy (FSHD) is caused by the mis-expression of the embryonic transcription factor DUX4 in skeletal muscle. A major mechanism of DUX4-induced cell toxicity in FSHD muscle is through the transcription of the HSATII pericentromeric repeats and their formation of single and double-stranded intranuclear ribonucleoprotein (RNP) complexes. In this proposal, we will determine the molecular components the RNP complexes and mechanisms of their cell toxicity. The significance of this proposal is that it will establish mechanisms of DUX4-induced pathology in FSHD muscle that will support future therapeutic interventions. The long-term goal of this project is to establish the mechanisms of DUX4-induced pathology in FSHD muscle. The overall hypothesis is that expression of DUX4 in FSHD muscle results in the accumulation of stable RNP complexes that alter the post-transcriptional regulation of other cellular RNAs and modulates the innate immune response pathways to inhibit the normal response to double-stranded RNAs. The specific aims of the proposal are: (Aim 1) Determine the RNAs and the proteins that comprise the intranuclear ribonucleoprotein complexes and their contribution to cell toxicity and genome instability. (Aim 2) Determine whether DUX4 regulates the selective degradation or translation of specific subsets of mRNAs. (Aim 3) Test the hypothesis that interactions between DUX4 and components of the innate immune response pathway represent a conserved function to modulate ISG induction by dsRNAs. Together, these aims will further establish the molecular basis of FSHD pathophysiology and identify new opportunities for future therapies.