Aging-disturbed FUS phase transition impairs hematopoietic stem cells by altering chromatin structure

• FUS^high 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. The molecular mechanisms behind this phenomenon are not fully understood. Here, we observed that the expression of FUS is increased in aged HSCs, and enforced FUS recapitulates the phenotype of aged HSCs through arginine-glycine-glycine–mediated aberrant FUS phase transition. By using Fus-gfp mice, we observed that FUS^high HSCs exhibit compromised FUS mobility and resemble aged HSCs both functionally and transcriptionally. The percentage of FUS^high HSCs is increased upon physiological aging and replication stress, and FUS^low HSCs of aged mice exhibit youthful function. Mechanistically, FUS^high HSCs exhibit a different global chromatin organization compared with FUS^low HSCs, which is observed in aged HSCs. Many topologically associating domains (TADs) are merged in aged HSCs because of the compromised binding of CCCTC-binding factor with chromatin, which is invoked by aberrant FUS condensates. It is notable that the transcriptional alteration between FUS^high and FUS^low HSCs originates from the merged TADs and is enriched in HSC aging-related genes. Collectively, this study reveals for the first time that aberrant FUS mobility promotes HSC aging by altering chromatin structure.