Posted by Friends of FSH Research on Jul 5, 2023
Report by Tessa Arends
See grant Consequence of human satellite II repeat expression in FSHD
My research addresses a relatively unexplored, yet major mechanism driving DUX4-induced cellular toxicity in skeletal muscle, the expression of pericentric human satellite repeat II (HSATII) repeats. We know that HSATII forms single- and double-stranded RNAs that are long-lived and can trigger an innate immune response, leading to cell death. However, little is known how HSATII RNA affects cellular function downstream of DUX4 expression. My work has uncovered that HSATII DNA and RNA are both capable of altering nuclear protein localization leading to disruption of cellular pathways.
I have found that that de-repression of HSATII regions sequesters epigenetic regulators resulting in impaired DNA damage response signaling. Enrichment of epigenetic modifiers at HSATII genomic regions results in global redistribution of histone post-translational modifications. Our data implicate HSATII de-repression and sequestration of protein complexes as a mechanism of regulating epigenetic and DNA repair pathways.
Additionally, I have found that HSATII RNA form unique complexes with several nuclear proteins that impact RNA metabolism pathways. HSATII RNA causes proteins to aggregate in DUX4-expressing muscle cells. These data suggest that HSATII RNA may sequester unique RNA binding proteins to illicit longer-term biological effects downstream of DUX4 expression.
Overall, my data suggest a dual function of HSATII expression – (1) regulation of RNA metabolism pathways via RNA-protein interactions and (2) global epigenetic reprogramming via DNA-protein interactions.