Disruption of YY1-mediated super-enhancer-promoter looping drives transcriptomic changes during mammalian stem-cell aging.

Stem-cell aging leads to a progressive decline in self-renewal and differentiation. How changes in chromatin architecture shape the gene-expression program underlying this loss of function remains incompletely understood. Here, we integrate transcriptomic, epigenomic, and Hi-C data from young and in-vitro-aged human mesenchymal stem cells (MSCs) to map super-enhancer-promoter (SE-promoter) loops and trace how they rewire during aging. SE target genes are enriched for Gene Ontology terms central to MSC identity and are disproportionately represented among age-regulated transcripts, suggesting that altered SE activity contributes to functional decline. YY1 is highly enriched at both promoters and SEs in young cells but is depleted from these loci in old cells. Loss of YY1 coincides with weakened Hi-C contacts, and YY1 knockdown in young MSCs recapitulates age-associated expression changes, especially among SE targets. Together, our results highlight YY1 as a key stabilizer of SE-promoter looping and gene-expression homeostasis during stem-cell aging.