Yin Yang 1 regulates cohesin complex protein SMC3 in mouse hematopoietic stem cells

Yin Yang 1 (YY1) and Structural Maintenance of Chromosomes 3 (SMC3) are two critical chromatin structural factors that mediate long-distance enhancer-promoter interactions and promote developmentally regulated changes in chromatin architecture in hematopoietic stem/progenitor cells (HSPCs). While YY1 plays critical functions in maintaining hematopoietic stem cell (HSC) quiescence, SMC3 is required for proper lineage differentiation. However, many questions remain unanswered regarding how YY1 and SMC3 interact with each other and impact hematopoiesis. We found that YY1 physically interacts with SMC3 and co-occupies with SMC3 at a large cohort of promoters genome-wide, and YY1 deficiency deregulates the genetic network governing cell metabolism. YY1 occupies the Smc3 promoter and represses SMC3 expression in HSPCs. While deletion of one Smc3 allele partially restores HSC numbers and quiescence in YY1 knockout mice, HSC self-renewal remains defective. YY1 regulates HSC metabolic pathways and maintains proper intracellular reactive oxygen species (ROS) levels in HSCs, and this regulation is independent of YY1- SMC3 axis. Our results establish a distinct YY1-SMC3 axis and its impact on HSC quiescence, self-renewal and metabolism