Consequence of human satellite repeat expression and immunostimulatory potential in FSHD

The project aims to provide a new mechanistic understanding of DUX4-driven pathogenesis of FSHD by investigating the impact of pericentric human satellite II (HSATII) RNA expression and aggregation. The overall hypothesis is that transcriptional activation of HSATII and subsequent RNA aggregation act as a molecular sink, sequestering nuclear regulatory proteins and exacerbating DUX4-mediated cellular dysregulation. Specific aims include determining the composition of HSATII-derived ribonucleoprotein complexes and their consequence on cell function, and elucidating the molecular mechanisms regulating HSATII regions. This work will utilize state-of-the-art molecular biology approaches and new targeting strategies to dissect FSHD disease pathology mediated by HSATII RNA aggregation and RNP formation, providing a basis for future studies.