FUShigh HSCs exhibit compromised FUS mobility and resemble aged HSCs both functionally and transcriptionally.
Aberrant FUS condensates diminish the binding of CTCF with chromatin and incite TAD-fusion events in aged HSCs.
Aged hematopoietic stem cells (HSCs) exhibit compromised reconstitution capacity. While, the molecular mechanisms behind this phenomenon are not fully understood. In this study, we observed that the expression of FUS is increased in aged HSCs and enforced FUS recapitulates the phenotype of aged HSCs through RGG-mediated aberrant FUS phase transition. By utilizing Fus-gfp mice, we observed that FUShigh HSCs exhibit compromised FUS mobility and resemble aged HSCs both functionally and transcriptionally. The percentage of FUShigh HSCs is increased upon physiological aging and replication stress, and FUSlow HSCs of aged mice exhibit youthful function. Mechanistically, FUShigh HSCs exhibit a different global chromatin organization compared to FUSlow HSCs, which is observed in aged HSCs. A large number of TADs are merged in aged HSCs due to the compromised binding of CTCF with chromatin, which is invoked by aberrant FUS condensates. It is notable that the transcriptional alteration between FUShigh and FUSlow HSCs originates from the merged TADs and are enriched in HSC aging-related genes. Collectively, this study for the first time reveals that aberrant FUS mobility promotes HSC aging by altering chromatin structure.