ENAGenomicsDick Lab, University Health Networkhttps://www.ebi.ac.uk/ena/browser/view/PRJNA668297Homo sapiensLife-long blood production requires long-term hematopoietic stem cells (LT-HSC) - marked by stemness states involving quiescence and self-renewal - to transition into activated short-term HSC (ST-HSC) with reduced stemness. As few transcriptional changes underlie this transition, we used single-cell and bulk ATAC-seq on human HSC and stem/progenitor subsets (HSPC) to uncover chromatin accessibility signatures, one including LT-HSC (LT/HSPC signature) and another excluding LT-HSC (Act/HSPC signature). These signatures inversely correlated during early hematopoietic commitment and differentiation. The Act/HSPC signature contains CTCF binding sites mediating 351 chromatin interactions, engaged in ST-HSC but not LT-HSC, enclosing multiple stemness pathway genes active in LT-HSC and repressed in ST-HSC. CTCF silencing derepressed stemness genes, restraining quiescent LT-HSC from transitioning to activated ST-HSC. Hence, 3D chromatin interactions centrally mediated by CTCF, endow a gatekeeper function that governs the earliest fate transitions HSC make by coordinating disparate stemness pathways linked to quiescence and self-renewal. Overall design: 2 Note from submitter: Raw data has been submitted separately to the EGA since it contains patient-sensitive informationxref:PubMed:33242413ENAHematopoietic Progenitor Cell, Hematopoietic Colony-Forming, Hematopoietic Colony-Forming Units, Hematopoietic, me75, Hematopoietic Progenitor, human being, Man (Taxonomy), cou, Genomes, Unit, Modern, Progenitor Cells, Colony-Forming Units, Stem Cells, Progenitor Cell, Colony Forming Units, whole genome, Hematopoietic Stem Cell, Tl3, Tl2, D17Mit170, human, Cell, Hematopoietic Progenitor Cells, Human, reaction, Lr, Colony-Forming Unit, Homo sapiens, Hematopoietic Stem, Stem Cell, Modern Man, Cells, Units, Bra, T1., Low, Man, Hematopoietic Colony-Forming UnitHematopoietic Progenitor Cell, Hematopoietic Colony-Forming, Hematopoietic Colony-Forming Units, Hematopoietic, me75, Hematopoietic Progenitor, human being, Man (Taxonomy), cou, Genomes, Unit, Modern, Progenitor Cells, Colony-Forming Units, Stem Cells, Progenitor Cell, Colony Forming Units, whole genome, Hematopoietic Stem Cell, Tl3, Tl2, D17Mit170, human, Cell, Hematopoietic Progenitor Cells, Human, reaction, Lr, Colony-Forming Unit, Homo sapiens, Hematopoietic Stem, Stem Cell, Modern Man, Cells, Units, Bra, T1., Low, Man, Hematopoietic Colony-Forming UnitfalseThe transition from quiescent to activated states in human hematopoietic stem cells is governed by dynamic 3D genome reorganization [Low-C]The transition from quiescent to activated states in human hematopoietic stem cells is governed by dynamic 3D genome reorganization [Low-C]2025-09-242020-12-09PRJNA668297GSE159287960633242413