Deep learning identifies Pbx1 as a network hub of hematopoietic stem cell aging [Pbx1 Cut&Tag]

Hematopoietic stem cells (HSCs) constitute a well-structured hematopoietic system that undergoes an age-related bias toward myeloid/platelet differentiation. The mechanism by which this aging hallmark is deeply embedded in intrinsic HSC programs is unknown. Using single-cell RNA-seq data, old HSCs harbor two distinct transcriptional programs: one shared with megakaryocytes and the other associated with the most primitive HSCs. By employing a transformer-based model that captures higher-order differences between young and aging HSCs and integrating time-series transcriptomic analyses, epigenetic studies, and comprehensive transcription factor screens, we identified Pbx1 as a central gene controlling both age-related transcriptional programs and differentiation defects in old HSCs. Pbx1 suppresses erythroid differentiation by repressing Gata1 expression. In addition, we found that the histone methyltransferase G9a/GLP acts as an epigenetic regulator that specifically inhibits Gata1 expression and erythroid differentiation. These findings provide insight into the differentiation defects associated with stem cell aging and potential strategies for rejuvenation.