Deep learning identifies Pbx1 as a network hub of hematopoietic stem cell aging [26hr ATAC-seq]

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.