Investigators: Tessa Arends PhD, Stephen Tapscott MD PhD
Category: Research - Basic
FSHD Scholar Grant
Facioscapulohumeral muscular dystrophy (FSHD) is the third most common form of muscular dystrophy that is caused by mis-expression of an early embryonic transcription factor DUX4 in skeletal muscle. DUX4 induces an early embryonic transcriptional program and activates transcription of LTR-retrotransposons, endogenous retrovirus elements and repetitive sequences. A major mechanism driving DUX4-mediated cellular toxicity in FSHD muscle is transcription of pericentric human satellite II (HSATII) repeats and subsequent formation of HSATII-derived ribonucleoprotein (RNP) complexes. The long-term goal of this proposal is to provide a new mechanistic understanding of DUX4-driven pathogenesis of FSHD and identify new disease biomarkers that will aid in the diagnosis of FSHD and design of promising therapeutics. The significance of this proposal is that it addresses a currently unexplored area in FSHD research – the impact of HSATII RNA expression in FSHD pathogenesis and disease. The overall hypothesis is that activation of HSATII and subsequent RNA aggregation act as a molecular sink to sequester nuclear regulatory proteins exacerbating DUX4-mediated cellular dysregulation. The specific aims of this proposal are: Determine the composition of HSATII-derived ribonucleoprotein complexes and the consequence of their formation on cell function (Aim 1) and elucidate the molecular mechanisms regulating HSATII regions (Aim 2). With the use of state-of-the-art molecular biology approaches and generation of new targeting strategies this proposal will be the first to dissect the mechanism(s) of FSHD disease pathology mediated by de-repression of HSATII and subsequent HSATII-RNP formation. Moreover, this work provides the basis for future studies of HSATII genome biology and function in human development and disease.