The transition from quiescent to activated states in human hematopoietic stem cells is governed by dynamic 3D genome reorganization [Low-C]

Life-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. 2 Note from submitter: Raw data has been submitted separately to the EGA since it contains patient-sensitive information

终身造血过程依赖于长期造血干细胞（long-term hematopoietic stem cells, LT-HSC）——这类细胞以具备细胞静止与自我更新能力的干细胞特性为核心特征——可分化为干细胞特性减弱的活化型短期造血干细胞（short-term hematopoietic stem cells, ST-HSC）。由于该转化过程仅伴随少量转录组水平变化，我们对人类造血干细胞及干/祖细胞亚群（hematopoietic stem/progenitor subsets, HSPC）开展了单细胞与批量转座酶可及性测序（ATAC-seq），以解析染色质可及性特征：其中一类特征包含LT-HSC（即LT/HSPC特征），另一类则不包含LT-HSC（即Act/HSPC特征）。上述两类特征在造血早期定向与分化过程中呈显著负相关。Act/HSPC特征包含可介导351种染色质相互作用的CCCTC结合因子（CTCF）结合位点，这类位点仅在ST-HSC中被激活而未见于LT-HSC，其调控区域涵盖多个在LT-HSC中活跃、在ST-HSC中被沉默的干细胞特性通路基因。沉默CTCF可解除对干细胞特性基因的转录抑制，阻止静止态LT-HSC向活化态ST-HSC转化。综上，由CTCF核心介导的三维染色质相互作用发挥了关键的守门人功能，通过协调与细胞静止及自我更新相关的多条干细胞特性通路，调控造血干细胞发生的最早期命运转化事件。2 提交者备注：由于原始数据包含患者敏感信息，已单独提交至EGA