[K99] Consequence of human satellite repeat expression and immunostimulatory potential in FSHD
Ente: National Institute of Arthritis and Musculoskeletal and Skin Diseases
Scadenza: 2027-08-31
Importo max: $124,308
Paese: US
Descrizione
PROJECT SUMMARY
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 transcriptional 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 HSATII RNA aggregation and subsequent
RNP formation. Moreover, this work provides the basis for future studies of HSATII genome biology and
function in human development and disease.
Istituzione: FRED HUTCHINSON CANCER CENTER
PI: Tessa Amanda Arends
Progetto: 5K99AR081926-02
Settori: National Institute of Arthritis and Musculoskeletal and Skin Diseases
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