Bcl11a orchestrates multilineage integrity in aging hematopoiesis by regulating multipotent progenitor fate decisions [ATAC-seq]

Aging hematopoiesis is characterized by myeloid skewing and impaired lymphoid output, a phenomenon traditionally attributed to intrinsic deterioration of hematopoietic stem cells (HSCs). Here, we demonstrate that aging-associated hematopoietic dysfunction is critically shaped at the level of multipotent progenitors (MPPs). We show that aging drives coordinated functional alterations across the MPP compartment, with expansion and reinforced myeloid output of MPP3 accompanied by functional attrition of lymphoid-primed MPP4, collectively exacerbating lineage imbalance. We identify Bcl11a as a dose-dependent regulator of MPP fate that preserves progenitor quiescence and lineage plasticity. Mechanistically, Bcl11a restrains premature myeloid activation by maintaining MPP3 quiescence through repression of the tyrosine kinase Fer, while simultaneously sustaining latent lymphoid potential via activation of the Irf8–Ebf1 transcriptional axis. Importantly, enhancing Bcl11a expression in aged mice restores balanced myeloid and lymphoid output, reprograms aging-associated transcriptional signatures, and rejuvenates multilineage hematopoietic function. Together, these findings establish Bcl11a as a central regulator of progenitor resilience during aging and identify MPPs as critical control points for preserving immune competence across the lifespan.