Arends Tessa, Bennett Sean R, Tapscott Stephen J
Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA 98109.
Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, WA 98109.
bioRxiv. 2025 Jan 22:2024.12.17.628988. doi: 10.1101/2024.12.17.628988.
RNA-driven protein aggregation leads to cellular dysregulation, disrupting normal cellular processes, and contributing to the development of diseases and tumorigenesis. Here, we show that double homeobox 4 (DUX4), an early embryonic transcription factor and causative gene of facioscapulohumeral muscular dystrophy (FSHD), induces the accumulation of stable intranuclear RNAs, including nucleolar RNA and human satellite II (HSATII) RNA. Stable intranuclear RNAs drive protein aggregation in DUX4-expressing muscle cells. Specifically, HSATII RNA sequesters RNA methylation factors. HSATII-YBX1 ribonucleoprotein (RNP) complex formation is mediated by HSATII double-stranded RNA and NSUN2 activity. Aberrant HSATII-RNP complexes affect RNA processing pathways, including RNA splicing. Differential splicing of genes mediated by HSATII-RNP complexes are associated with pathways known to be dysregulated by DUX4 expression. These findings highlight the broader influence of DUX4 on nuclear RNA dynamics and suggest that HSATII RNA could be a critical mediator of RNA processing regulation. Understanding the impact of HSATII-RNP formation on RNA processing provides insight into the molecular mechanisms underlying FSHD.
RNA驱动的蛋白质聚集导致细胞失调，扰乱正常细胞过程，并促进疾病发展和肿瘤发生。在此，我们表明双同源盒4（DUX4），一种早期胚胎转录因子及面肩肱型肌营养不良症（FSHD）的致病基因，可诱导稳定的核内RNA积累，包括核仁RNA和人类卫星II（HSATII）RNA。稳定的核内RNA在表达DUX4的肌肉细胞中驱动蛋白质聚集。具体而言，HSATII RNA隔离RNA甲基化因子。HSATII-YBX1核糖核蛋白（RNP）复合物的形成由HSATII双链RNA和NSUN2活性介导。异常的HSATII-RNP复合物影响RNA加工途径，包括RNA剪接。由HSATII-RNP复合物介导的基因差异剪接与已知因DUX4表达而失调的途径相关。这些发现凸显了DUX4对核RNA动态的更广泛影响，并表明HSATII RNA可能是RNA加工调控的关键介质。了解HSATII-RNP形成对RNA加工的影响有助于深入了解FSHD的分子机制。
