GSE110440
Investigation of mRNA expression pattern by RAD21 knockdown in hematopoetic stem cells
Elevated inflammation represents a hallmark of hematopoietic aging and leukemia development but mechanistically its impact on hematopoietic stem and progenitor cell (HSPC) maintenance remains incompletely understood. Here we identify Rad21/cohesin as a major component mediating inflammation-induced NF-kB signaling, which in turn limits self-renewal of HSPCs by induction of differentiation. Disruption of Rad21/cohesin diminishes inflammation-induced loss of self-renewal and induction of differentiation, but these effects are abrogated in NF-kB knockout (p50-/-) HSPCs. During aging, HSPCs exhibit an increased responsiveness to activate NF-kB signaling in response to inflammatory stimuli also resulting in activation of genes encoding for secreted cytokines. These cell intrinsic and extrinsic responses cooperatively enhance differentiation and loss of self-renewal of HSPCs resulting in increased selection of Rad21/cohesin deficient HSPCs exhibiting elevated self-renewal and myeloid skewed differentiation. Together, these results identify cohesin-mediated NF-kB signaling as a major axis connecting cell extrinsic increases in inflammation with the evolution of hallmark features HSC aging characterized by increases in self renewal and myeloid skewed differentiation aggravated by the concomitant selection of cohesin deficient HSPCs. Overall design: total samples: 12 (6 in vivo: 3 Rad21 knockdown, 3 control; 6 in vitro: 3 Rad21 knockdown, 3 control)