Update: Consequence of human satellite II repeat expression in FSHD

Posted by Friends of FSH Research on Jan 27, 2025

Report by Tessa Arends
See grant Consequence of human satellite II repeat expression in FSHD

My research investigates a key mechanism underlying DUX4-induced toxicity in skeletal muscle: the expression of pericentromeric human satellite II (HSATII) repeats. Our lab has demonstrated that DUX4 activates bidirectional transcription of HSATII, resulting in the formation of intranuclear RNA aggregates. These HSATII RNA aggregates sequester nuclear proteins forming HSATII-derived ribonucleoprotein (RNP) complexes, thereby contributing to DUX4-driven cellular toxicity in muscle cells. I have used discovery-based approaches, including proteomics, to identify proteins that associate with HSATII RNA. My findings indicate selective interactions of RNA binding proteins, including proteins known to be aggregated in FSHD muscle cells and RNA methylation factors, with HSATII RNA which impacts RNA processing pathways, leading to differential splicing of genes downstream of DUX4 expression which are implicated in FSHD pathology. Additionally, my work has identified a network of transcriptional and epigenetic factors that may regulate HSATII regions. Importantly, the results from these studies will uncover how HSATII expression contributes to epigenetic reprogramming downstream of DUX4.