Single-cell chromatin accessibility data using scATAC-seq

A single hematopoietic stem cell can give rise to all blood cells with remarkable fidelity. Here, we define the chromatin accessibility and transcriptional landscape controlling this process in thirteen primary cell types that traverse the hematopoietic hierarchy. Exploiting the finding that enhancer landscapes better reflect cell identity than mRNA levels, we enable "enhancer cytometry" for accurate enumeration of pure cell types from complex populations. We further reveal the lineage ontogeny of genetic elements linked to diverse human diseases. In acute myeloid leukemia, chromatin accessibility reveals distinctive regulatory evolution in pre-leukemic HSCs (pHSCs), leukemia stem cells, and leukemic blasts. These leukemic cells demonstrate unique lineage infidelity, confirmed by single cell regulomes. We further show that pHSCs have a competitive advantage that is conferred by reduced chromatin accessibility at HOXA9 targets and is associated with adverse patient outcomes. Thus, regulome dynamics can provide diverse insights into human hematopoietic development and disease.

单个造血干细胞（hematopoietic stem cell）可高保真地生成所有血细胞类型。本研究针对贯穿造血层级的13种原代细胞类型，解析了调控该过程的染色质可及性（chromatin accessibility）与转录调控景观。研究团队基于增强子景观较mRNA水平更能反映细胞身份这一发现，建立了“增强子细胞计量术（enhancer cytometry）”，可从复杂细胞群体中精准枚举纯细胞类型。本研究还揭示了与多种人类疾病相关的遗传元件的谱系发生过程。在急性髓系白血病中，染色质可及性分析揭示了白血病前期造血干细胞（pre-leukemic HSCs, pHSCs）、白血病干细胞（leukemia stem cells）与白血病原始细胞的独特调控演化特征。这些白血病细胞展现出独特的谱系保真度异常，该特征经单细胞调控组（single cell regulomes）分析得以证实。本研究进一步证实，白血病前期造血干细胞具有竞争优势：该优势源于HOXA9靶位点的染色质可及性降低，且与患者不良预后相关。综上，调控组动态变化可为人类造血发育与疾病研究提供多维度的洞察。