DUX4-induced HSATII RNA accumulation drives protein aggregation, impacting RNA processing pathways

Area of Science:

• Molecular Biology
• Genetics
• Cellular Biology

Background:

• RNA-driven protein aggregation contributes to disease and tumorigenesis.
• Double homeobox 4 (DUX4) is an embryonic transcription factor linked to facioscapulohumeral muscular dystrophy (FSHD).

Purpose of the Study:

• To investigate how DUX4 influences nuclear RNA dynamics and protein aggregation in muscle cells.
• To elucidate the role of human satellite II (HSATII) RNA in DUX4-mediated cellular dysregulation.

Main Methods:

• Analysis of intranuclear RNA accumulation induced by DUX4.
• Investigation of RNA methylation factor sequestration by HSATII RNA.
• Characterization of HSATII-YBX-1 ribonucleoprotein (RNP) complex formation.
• Assessment of RNA splicing alterations due to HSATII-RNP complexes.

Main Results:

• DUX4 induces accumulation of stable intranuclear RNAs, including HSATII RNA, promoting protein aggregation in muscle cells.
• HSATII RNA sequesters RNA methylation factors and forms complexes with YBX-1, mediated by NSUN2 activity.
• Aberrant HSATII-RNP complexes disrupt RNA processing pathways, notably differential gene splicing.
• DUX4-mediated differential splicing is linked to known dysregulated pathways in FSHD.

Conclusions:

• DUX4 significantly impacts nuclear RNA dynamics, with HSATII RNA acting as a key mediator.
• HSATII-RNP complex formation dysregulates RNA processing, offering insights into FSHD molecular mechanisms.