1.The transition from quiescent to activated states in human hematopoietic stem cells is governed by dynamic 3D genome reorganization.
1.The transition from quiescent to activated states in human hematopoietic stem cells is governed by dynamic 3D genome reorganization.
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1.人类造血干细胞从静止状态到激活状态的转变是由动态3D基因组重组控制的。
DOI：
10.1016/j.stem.2020.11.001
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发表时间：
2021
期刊：
影响因子：
23.9
通讯作者：
et al
中科院分区：
文献类型：
--
作者：
Naoya Takayama;et al
终生的血液生产需要长期的造血干细胞(LT-HSCs)，以干细胞状态为标志，包括静止和自我更新，以转化为激活的短期HSCs，但干细胞数量减少。由于这种转变背后的转录变化很少，我们使用单细胞和批量分析转座酶可访问染色质测序(ATAC-SEQ)来揭示人HSCs和造血干细胞(HSPC)亚群的染色质可及性特征，一个包括LT-HSCs(LT/HSPC特征)，另一个排除LT-HSCs(激活的HSPC[Act/HSPC]特征)。在早期的造血承诺和分化过程中，这些信号呈负相关。Act/HSPC信号包含CCCTC结合因子(CTCF)结合位点，介导ST-HSCs参与的351个染色质相互作用，而不是LT-HSCs，包含在LT-HSCs中活跃的和在ST-HSCs中抑制的多个茎干途径基因。CTCF沉默去抑制的茎基因，抑制静止的LT-HSC向激活的ST-HSCs的转变。因此，由CTCF集中调节的3D染色质相互作用赋予了门卫功能，通过协调与静止和自我更新相关的不同茎干途径，调控HSC进行的最早命运转移。
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.