Yy1^−/−LSKs exhibit an aberrant genetic network with corruption of genes involved in HSC metabolism. RNA-seq–based comparison of gene expression in sorted Yy1^+/+, Yy1^−/−, and Yy1^−/−Smc3^+/− LSK cells. (A-B) Gene set enrichment analysis of genes deregulated in Yy1^−/−vs Yy1^+/+, Yy1^−/−Smc3^+/− vs Yy1^+/+, and Yy1^−/−Smc3^+/− vs Yy1^−/−. Enriched biological processes are shown with corresponding adjusted P values (A). Genes involved in metabolism and HSPCs are enriched in Yy1^−/−and Yy1^−/−Smc3^+/− LSK cells compared with Yy1^+/+ (B). (C) Heat map depicting selected upregulated and downregulated genes involved in regulation of HSPC function based on transcript per million. The green boxes label the genes involved in metabolism pathway. (D) mRNA expression levels of genes that are critical for metabolism and HSC functions based on the transcript per million of RNA-seq. (E) YY1, cohesion, and CTCF occupancy at the promoters of genes that are critical for HSC function and metabolism. (F) Increased intracellular ROS levels in Yy1^−/−and Yy1^−/−Smc3^+/− HSCs. (G) Schematic diagram shows that YY1 represses SMC3 expression and interacts with SMC3 to facilitate chromatin structures of genes that are critical for HSC metabolism. In YY1-deficient HSCs, SMC3 is upregulated and interacts with CTCF, which leads to changes of chromatin conformation and altered metabolic gene expression. N represents the number of mice; data are presented as means ± SD; ∗P < .05 ∗∗P < .01, and ∗∗∗P < .001.