Lifelong blood production requires long-term hematopoietic stem cells (LT-HSCs), marked by stemness states involving quiescence and self-renewal, to transition into activated short-term HSCs (ST-HSCs) with reduced stemness. As few transcriptional changes underlie this transition, we used single-cell and bulk assay for transposase-accessible chromatin sequencing (ATAC-seq) on human HSCs and hematopoietic stem and progenitor cell (HSPC) subsets to uncover chromatin accessibility signatures, one including LT-HSCs (LT/HSPC signature) and another excluding LT-HSCs (activated HSPC [Act/HSPC] signature). These signatures inversely correlated during early hematopoietic commitment and differentiation. The Act/HSPC signature contains CCCTC-binding factor (CTCF) binding sites mediating 351 chromatin interactions engaged in ST-HSCs, but not LT-HSCs, enclosing multiple stemness pathway genes active in LT-HSCs and repressed in ST-HSCs. CTCF silencing derepressed stemness genes, restraining quiescent LT-HSCs from transitioning to activated ST-HSCs. Hence, 3D chromatin interactions centrally mediated by CTCF endow a gatekeeper function that governs the earliest fate transitions HSCs make by coordinating disparate stemness pathways linked to quiescence and self-renewal.

终生造血需要长期造血干细胞 (LT-HSC)，其标志是干性状态，包括静止和自我更新，才能转变为干性降低的活化短期 HSC (ST-HSC)。由于很少有转录变化是这种转变的基础，我们使用单细胞和批量测定对人类 HSC 和造血干祖细胞 (HSPC) 亚群进行转座酶可及染色质测序 (ATAC-seq) 以揭示染色质可及性特征，其中包括 LT- HSC（LT/​​HSPC 签名）和另一个不包括 LT-HSC（激活的 HSPC [Act/HSPC] 签名）。这些特征在早期造血承诺和分化过程中呈负相关。Act/HSPC 签名包含 CCCTC 结合因子 (CTCF) 结合位点，介导 351 个染色质相互作用参与 ST-HSC，但不参与 LT-HSC，包含在 LT-HSCs 中活跃并在 ST-HSCs 中被抑制的多个干性通路基因。CTCF 沉默去抑制的干性基因，抑制静止的 LT-HSCs 转变为活化的 ST-HSCs。因此，由 CTCF 集中介导的 3D 染色质相互作用赋予了一种看门人功能，该功能通过协调与静止和自我更新相关的不同干性通路来控制 HSC 进行的最早的命运转变。