Chromatin factor YY1 controls fetal hematopoietic stem cell migration and engraftment in mice [CUT&Tag]

Fetal liver is a major organ for generating hematopoietic stem cells (HSCs) during embryonic development. Many questions remain unanswered regarding how transition of hematopoiesis from the fetal liver to the bone marrow (BM) is regulated. We demonstrate that mammalian Polycomb Group (PcG) protein Yin Yang 1 (YY1) is required for this transition, as a conditional knockout of Yy1 in the hematopoietic system during fetal development results in exhaustion of fetal HSC pools and neonatal death. Yy1 deficient fetal HSCs have diminished capacity to migrate to and engraft the adult BM, and consequently fail to reconstitute blood. YY1 deficiency leads to distinct transcriptomic changes in fetal hematopoietic stem progenitor cells (HSPCs) compared with adult HSPCs. The genetic networks governing cell motility and adhesion are distinctly deregulated by YY1 in fetal HSPCs. Notably, YY1 regulates mobility of fetal HSPCs largely through an indirect mechanism as it does not directly bind to the promoters of dysregulated genes involved in control of mobility. Instead, it regulates broader transcriptional mechanisms by modulating the genes in chromatin remodeling complexes that impact HSPC mobility. Our study provides a framework to further decipher how temporal epigenomic configurations determine HSC fetal-to-adult transition during development.