Progress Update: Consequence of human satellite II repeat expression in FSHD

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

My research addresses a major mechanism driving DUX4-induced cellular toxicity in skeletal muscle, the formation and aggregation of RNA-protein complexes. Our lab has shown that DUX4 induces bidirectional transcription of pericentromeric human satellite II (HSATII) repeats which form single-stranded and doublestranded RNA aggregates. HSATII RNA aggregates have been shown to sequester nuclear proteins and contributes to DUX4-mediated cellular toxicity in muscle cells. Interestingly, bidirectional transcription of pericentric satellites is not unique to DUX4-expressing human myoblast cells, but also observed in mouse and human development, where mouse Dux and human DUX4 are briefly expressed. This suggests differential regulatory roles of HSATII depending on HSATII RNA structure. 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 with HSATII RNA, which may impact mRNA processing pathways downstream of DUX4 expression; and that HSATII RNA structure dictates protein recruitment.