DRP004627
Bmi1 counteracts hematopoietic stem cell aging by suppressing ectopic activation of bivalent domains and developmental genes
Polycomb-group (PcG) proteins are essential for stem cell regulation. We previously demonstrated Bmi1, a component of PcG complexes, could enhance the regenerative capacity of hematopoietic stem cells (HSCs). Here we challenged to encounter age-related loss of stem cell functions by persistent expression of Bmi1. Bmi1 contributes to maintain reconstitutive capacity in aged HSCs, whereas it did not change differentiation skew towards myeloid hematopoiesis along aging. The single cell BMT unveiled that Bmi1 was not likely to alter functional HSCs numerically, but enhance the self-renewal ability of each single HSC. Respecting the mechanisms through which Bmi1 enforce the regenerative capacity of stem cell, we identified 227 bivalent domains including hematopoietic lineage moderator or developmental regulator loci as direct targets of Bmi1. Part of these target genes were shown to be ectopically derepressed in aged mice HSCs, leading to HSC derailment. Persistent expression of Bmi1 maintained transcriptional repression of these domains throughout aging, which prevented the age-related loss of stem cell capacity. Thus, forced expression of Bmi1 is potential approach to confront the alteration of self-renewal capacity of HSCs along aging.