Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Harvard Society of Fellows, Harvard University, Cambridge, MA 02138, USA.
Center for Personal Dynamic Regulomes, Stanford University, Stanford, CA 94305, USA.
Cell. 2018 May 31;173(6):1535-1548.e16. doi: 10.1016/j.cell.2018.03.074. Epub 2018 Apr 26.
Human hematopoiesis involves cellular differentiation of multipotent cells into progressively more lineage-restricted states. While the chromatin accessibility landscape of this process has been explored in defined populations, single-cell regulatory variation has been hidden by ensemble averaging. We collected single-cell chromatin accessibility profiles across 10 populations of immunophenotypically defined human hematopoietic cell types and constructed a chromatin accessibility landscape of human hematopoiesis to characterize differentiation trajectories. We find variation consistent with lineage bias toward different developmental branches in multipotent cell types. We observe heterogeneity within common myeloid progenitors (CMPs) and granulocyte-macrophage progenitors (GMPs) and develop a strategy to partition GMPs along their differentiation trajectory. Furthermore, we integrated single-cell RNA sequencing (scRNA-seq) data to associate transcription factors to chromatin accessibility changes and regulatory elements to target genes through correlations of expression and regulatory element accessibility. Overall, this work provides a framework for integrative exploration of complex regulatory dynamics in a primary human tissue at single-cell resolution.
人类造血涉及多能细胞向谱系限制状态的细胞分化。虽然这个过程的染色质可及性图谱已经在特定的群体中得到了探索，但单细胞调节变化因总体平均而被隐藏。我们收集了 10 个人类免疫表型定义的造血细胞类型的单细胞染色质可及性图谱，并构建了人类造血的染色质可及性图谱，以描述分化轨迹。我们发现与多能细胞类型中不同发育分支的谱系偏向一致的变异。我们观察到常见髓系祖细胞（CMP）和粒细胞-巨噬细胞祖细胞（GMP）中的异质性，并开发了一种沿着其分化轨迹划分 GMP 的策略。此外，我们整合了单细胞 RNA 测序（scRNA-seq）数据，通过表达和调节元件可及性的相关性，将转录因子与染色质可及性变化以及调节元件与靶基因联系起来。总的来说，这项工作为在单细胞分辨率下对原发性人类组织中的复杂调节动态进行综合探索提供了一个框架。
